Halo-substituted piperidines as orexin receptor modulators

ABSTRACT

The present application relates to certain halo-substituted piperidine compounds, pharmaceutical compositions containing them, and methods of using them, including methods for treating substance addiction, panic disorder, anxiety, post-traumatic stress disorder, pain, depression, seasonal affective disorder, an eating disorder, or hypertension.

RELATED APPLICATIONS

This application claims the benefit of priority to U.S. ProvisionalPatent Application No. 62/294,940, filed Feb. 12, 2016, and U.S.Provisional Patent Application No. 62/336,102, filed May 13, 2016, whichapplications are hereby incorporated by reference in their entirety.

STATEMENT OF GOVERNMENT SUPPORT

This invention was made with government support under Grant Numbers 1P01DA033622 and 1 U01 NS083614 awarded by the National Institutes ofHealth. The government has certain rights in this invention.

BACKGROUND

Orexins are a family of homologous peptides including species orexin A,or OR-A, and orexin B, or OR-B. Orexin A is a 33 amino acid peptide andorexin B is a 28 amino acid peptide (Sakurai T. et al., Cell (1998), 92,573-585). Orexins are produced in neurons of the lateral hypothalamusand bind to at least two distinct G-protein-coupled receptors, termedOX₁ and OX₂ receptors. The OX₁ receptor is selective for OR-A, while theOX₂ receptor can bind both OR-A and OR-B. Orexins are found to stimulatefood consumption, regulate states of sleep and wakefulness, and may beinvolved in neural mechanisms of drug abuse and addiction.

Orexin receptors are suitable targets for the development of drugcandidates for the treatment of a variety of Orexin-related pathologiesor symptoms, such as, but not limited to, sleep/wake disorders, anxiety,and obesity. Numerous modulators of OX₁, OX₂, or both, have beendeveloped to date [J. Med. Chem. 2016, 59(2), 504-530]. However, many ofthe reported Orexin receptor modulators, such as antagonist ligands,have suboptimal metabolic stabilities. This translates into shorthalf-lives and high observed clearance in in vivo pharmacokineticexperiments (ChemMedChem, 2012, 7, 415-424; Bioorganic&MedicinalChemistry Letters 2012, 22, 3890-3894; Bioorganic&Medicinal ChemistryLetters, 2015, 25, 1884-1891; J. Med. Chem. 2015, 58, 5620-5636.). Thereremains a need for small molecule modulators of Orexin receptors withdesirable pharmaceutical properties.

SUMMARY OF THE APPLICATION

This application provides a compound of formula (I),

or its pharmaceutically acceptable salt hereof, wherein:

X is halogen, such as F;

X′ is H or halogen, such as F;

Z is NR² or O;

A is aryl, aroyl, heteroaryl, or heteroaroyl, wherein A is optionallysubstituted with one or more substituents independently selected fromthe group consisting of alkyl, such as C₁₋₄alkyl (e.g., methyl, ethyl,—CHF₂, or —CF₃); cycloalkyl; halo, such as —F, —Cl, or —Br (e.g., —Cl);—OH; alkoxy, such as methoxy; —CN; —NR^(a)R^(b); —N(R^(a))C(O) alkyl;—N(R^(a))CO₂alkyl; —N(R^(a))SO₂alkyl; —C(O)alkyl; —CO₂H; —CO₂alkyl;—CONR^(a)R^(b); —SO₂alkyl; and —SO₂NR^(a)R^(b); wherein R^(a) and R^(b)are independently for each occurrence H or alkyl;

B is aryl or heteroaryl, wherein B is optionally substituted with one ormore substituents independently selected from the group consisting ofalkyl, such as C₁₋₄alkyl (e.g., methyl, ethyl, isopropyl, —CH₂CF₃,—CHF₂, or —CF₃); cycloalkyl; halo, such as —F, —Cl, or —Br (e.g., —F or—Cl); —OH; alkoxy, such as methoxy or isopropoxy (e.g., methoxy); —CN;—NR^(c)R^(d); —N(R^(c))C(O) alkyl; —N(R^(c))CO₂alkyl; —N(R^(c))SO₂alkyl;—C(O)alkyl; —CO₂H; —CO₂alkyl; —CONR^(c)R^(d); —SO₂alkyl; and—SO₂NR^(c)R^(d); wherein R^(c) and R^(d) are independently for eachoccurrence H or alkyl;

E is aryl or heteroaryl, wherein E is optionally substituted with one ormore substituents independently selected from the group consisting ofalkyl, such as C₁₋₄alkyl (e.g., methyl, ethyl, —CHF₂, or —CF₃);cycloalkyl; halo, such as —F, —Cl, or —Br (e.g., —F or —Cl); —OH;alkoxy, such as methoxy; —CN; —NR^(e)R^(f); —N(R^(e))C(O) alkyl;—N(R^(e))CO₂alkyl; —N(R^(e))SO₂alkyl; —C(O)alkyl; —CO₂H; —CO₂alkyl;—CONR^(e)R^(f); —SO₂alkyl; and —SO₂NR^(e)R^(f); wherein R^(e) and R^(f)are independently for each occurrence H or alkyl;

n is 1, 2, or 3;

R¹ is alkyl, such as C₁₋₄alkyl (e.g., methyl); and

R² is H or alkyl, such as C₁₋₄alkyl (e.g., methyl).

In certain embodiments, A is aryl or heteroaryl, wherein A is optionallysubstituted with one or more substituents independently selected fromthe group consisting of alkyl, such as C₁₋₄ alkyl (e.g., methyl, ethyl,—CHF₂, or —CF₃); cycloalkyl; halo, such as —F, —Cl, or —Br (e.g., —Cl);—OH; alkoxy, such as methoxy; —CN; —NR^(a)R^(b); —N(R^(a))C(O) alkyl;—N(R^(a))CO₂alkyl; —N(R^(a))SO₂alkyl; —C(O)alkyl; —CO₂H; —CO₂alkyl;—CONR^(a)R^(b); —SO₂alkyl; and —SO₂NR^(a)R^(b); wherein R^(a) and R^(b)are independently for each occurrence H or alkyl.

In certain embodiments, n is 1.

In certain embodiments, X′ is halogen, such as F.

In certain embodiments, the compound of formula (I) can be representedby formula (Ia),

or a pharmaceutically acceptable salt thereof, wherein

X is halogen, such as F;

X′ is H or halogen, such as F;

Z is NR² or O;

A is aryl, aroyl, heteroaryl, or heteroaroyl, wherein A is optionallysubstituted with one or more substituents independently selected fromthe group consisting of alkyl, such as C₁₋₄alkyl (e.g., methyl, ethyl,—CHF₂, or —CF₃); cycloalkyl; halo, such as —F, —Cl, or —Br (e.g., —Cl);—OH; alkoxy, such as methoxy; —CN; —NR^(a)R^(b); —N(R^(a))C(O) alkyl;—N(R^(a))CO₂alkyl; —N(R^(a))SO₂alkyl; —C(O)alkyl; —CO₂H; —CO₂alkyl;—CONR^(a)R^(b); —SO₂alkyl; and —SO₂NR^(a)R^(b); wherein R^(a) and R^(b)are independently for each occurrence H or alkyl;

B is aryl or heteroaryl, wherein B is optionally substituted with one ormore substituents independently selected from the group consisting ofalkyl, such as C₁₋₄alkyl (e.g., methyl, ethyl, isopropyl, —CH₂CF₃,—CHF₂, or —CF₃); cycloalkyl; halo, such as —F, —Cl, or —Br (e.g., —F or—Cl); —OH; alkoxy, such as methoxy or isopropoxy (e.g., methoxy); —CN;—NR^(c)R^(d); —N(R^(c))C(O) alkyl; —N(R^(c))CO₂alkyl; —N(R^(c))SO₂alkyl;—C(O)alkyl; —CO₂H; —CO₂alkyl; —CONR^(c)R^(d); —SO₂alkyl; and—SO₂NR^(c)R^(d); wherein R^(c) and R^(d) are independently for eachoccurrence H or alkyl;

E is aryl or heteroaryl, wherein E is optionally substituted with one ormore substituents independently selected from the group consisting ofalkyl, such as C₁₋₄alkyl (e.g., methyl, ethyl, —CHF₂, or —CF₃);cycloalkyl; halo, such as —F, —Cl, or —Br (e.g., —F or —Cl); —OH;alkoxy, such as methoxy; —CN; —NR^(e)R^(f); —N(R^(e))C(O) alkyl;—N(R^(e))CO₂alkyl; —N(R^(e))SO₂alkyl; —C(O)alkyl; —CO₂H; —CO₂alkyl;—CONR^(e)R^(f); —SO₂alkyl; and —SO₂NR^(e)R^(f); wherein R^(e) and R^(f)are independently for each occurrence H or alkyl;

n is 1, 2, or 3;

R¹ is alkyl, such as C₁₋₄alkyl (e.g., methyl); and

R² is H or alkyl, such as C₁₋₄alkyl (e.g., methyl).

In certain embodiments, A is aryl or heteroaryl, wherein A is optionallysubstituted with one or more substituents independently selected fromthe group consisting of alkyl, such as C₁₋₄ alkyl (e.g., methyl, ethyl,—CHF₂, or —CF₃); cycloalkyl; halo, such as —F, —Cl, or —Br (e.g., —Cl);—OH; alkoxy, such as methoxy; —CN; —NR^(a)R^(b); —N(R^(a))C(O) alkyl;—N(R^(a))CO₂alkyl; —N(R^(a))SO₂alkyl; —C(O)alkyl; —CO₂H; —CO₂alkyl;—CONR^(a)R^(b); —SO₂alkyl; and —SO₂NR^(a)R^(b); wherein R^(a) and R^(b)are independently for each occurrence H or alkyl.

In certain embodiments, n is 1.

In certain embodiments, X′ is halogen, such as F.

In certain embodiments, the compound of formula (I) can be representedby formula (Ib),

or a pharmaceutically acceptable salt thereof, wherein

Z is NR² or O;

A is aryl, aroyl, heteroaryl, or heteroaroyl, wherein A is optionallysubstituted with one or more substituents independently selected fromthe group consisting of alkyl, such as C₁₋₄alkyl (e.g., methyl, ethyl,—CHF₂, or —CF₃); cycloalkyl; halo, such as —F, —Cl, or —Br (e.g., —Cl);—OH; alkoxy, such as methoxy; —CN; —NR^(a)R^(b); —N(R^(a))C(O) alkyl;—N(R^(a))CO₂alkyl; —N(R^(a))SO₂alkyl; —C(O)alkyl; —CO₂H; —CO₂alkyl;—CONR^(a)R^(b); —SO₂alkyl; and —SO₂NR^(a)R^(b); wherein R^(a) and R^(b)are independently for each occurrence H or alkyl;

B is aryl or heteroaryl, wherein B is optionally substituted with one ormore substituents independently selected from the group consisting ofalkyl, such as C₁₋₄alkyl (e.g., methyl, ethyl, isopropyl, —CH₂CF₃,—CHF₂, or —CF₃); cycloalkyl; halo, such as —F, —Cl, or —Br (e.g., —F or—Cl); —OH; alkoxy, such as methoxy or isopropoxy (e.g., methoxy); —CN;—NR^(c)R^(d); —N(R^(c))C(O) alkyl; —N(R^(c))CO₂alkyl; —N(R^(c))SO₂alkyl;—C(O)alkyl; —CO₂H; —CO₂alkyl; —CONR^(c)R^(d); —SO₂alkyl; and—SO₂NR^(c)R^(d); wherein R^(c) and R^(d) are independently for eachoccurrence H or alkyl;

E is aryl or heteroaryl, wherein E is optionally substituted with one ormore substituents independently selected from the group consisting ofalkyl, such as C₁₋₄alkyl (e.g., methyl, ethyl, —CHF₂, or —CF₃);cycloalkyl; halo, such as —F, —Cl, or —Br (e.g., —F or —Cl); —OH;alkoxy, such as methoxy; —CN; —NR^(e)R^(f); —N(R^(e))C(O) alkyl;—N(R^(e))CO₂alkyl; —N(R^(e))SO₂alkyl; —C(O)alkyl; —CO₂H; —CO₂alkyl;—CONR^(e)R^(f); —SO₂alkyl; and —SO₂NR^(e)R^(f); wherein R^(e) and R^(f)are independently for each occurrence H or alkyl;

n is 1, 2, or 3;

R¹ is alkyl, such as C₁₋₄alkyl (e.g., methyl); and

R² is H or alkyl, such as C₁₋₄alkyl (e.g., methyl).

In certain embodiments, A is aryl or heteroaryl, wherein A is optionallysubstituted with one or more substituents independently selected fromthe group consisting of alkyl, such as C₁₋₄ alkyl (e.g., methyl, ethyl,—CHF₂, or —CF₃); cycloalkyl; halo, such as —F, —Cl, or —Br (e.g., —Cl);—OH; alkoxy, such as methoxy; —CN; —NR^(a)R^(b); —N(R^(a))C(O) alkyl;—N(R^(a))CO₂alkyl; —N(R^(a))SO₂alkyl; —C(O)alkyl; —CO₂H; —CO₂alkyl;—CONR^(a)R^(b); —SO₂alkyl; and —SO₂NR^(a)R^(b); wherein R^(a) and R^(b)are independently for each occurrence H or alkyl.

In certain embodiments, n is 1.

In certain embodiments, the compound of formula (I) can be representedby formula (II):

or a pharmaceutically acceptable salt thereof, wherein:

m=1, 2, or 3; and

R⁵ represents alkyl, cycloalkyl, halo, —OH, alkoxy, —CN, —NR^(j)R^(k),—N(R^(j))C(O) alkyl, —N(R^(j))CO₂alkyl, —N(R^(j))SO₂alkyl, —C(O)alkyl,—CO₂H, —CO₂alkyl, —CONR^(j)R^(k), —SO₂alkyl, or —SO₂NR^(j)R^(k); whereinR^(j) and R^(k) are independently for each occurrence H or alkyl; and

X, X′, Z, B, E, n, R¹ and R² are as defined herein.

In certain such embodiments, the compound of formula (II) can berepresented by formula (IIa),

or a pharmaceutically acceptable salt thereof. In certain suchembodiments, X and X′ are both F.

In certain embodiments, the compound of formula (I) can be representedby formula (III):

or a pharmaceutically acceptable salt thereof; wherein:

m=1, 2, 3, or 4; and

R⁵ represents alkyl, cycloalkyl, halo, —OH, alkoxy, —CN, —NR^(j)R^(k),—N(R^(j))C(O) alkyl, —N(R^(j))CO₂alkyl, —N(R^(j))SO₂alkyl, —C(O)alkyl,—CO₂H, —CO₂alkyl, —CONR^(j)R^(k), —SO₂alkyl, or —SO₂NR^(j)R^(k); whereinR^(j) and R^(k) are independently for each occurrence H or alkyl; and

X, X′, Z, B, E, n, R¹ and R² are as defined herein.

In certain such embodiments, the compound of formula (III) can berepresented by formula (IIIa),

or a pharmaceutically acceptable salt thereof. In certain suchembodiments, X and X′ are both F.

In certain embodiments, the compound of formula (I) can be representedby formula (IV):

or a pharmaceutically acceptable salt thereof; wherein:

R⁶ represents alkyl, cycloalkyl, halo, —OH, alkoxy, —CN, —NR^(o)R^(p),—N(R^(o))C(O) alkyl, —N(R^(p))CO₂alkyl, —N(R^(o))SO₂alkyl, —C(O)alkyl,—CO₂H, —CO₂alkyl, —CONR^(o)R^(p), —SO₂alkyl, or —SO₂NR^(o)R^(p); whereinR^(o) and R^(p) are independently for each occurrence H or alkyl; and

X, X′, Z, A, E, n, R¹ and R² are as defined herein.

In certain such embodiments, the compound of formula (IV) can berepresented by formula (IVa),

or a pharmaceutically acceptable salt thereof. In certain suchembodiments, X and X′ are both F.

In certain embodiments, the compound of formula (I) can be representedby formula (V):

or a pharmaceutically acceptable salt thereof; wherein:

R⁶ represents alkyl, cycloalkyl, halo, —OH, alkoxy, —CN, —NR^(o)R^(p),—N(R^(o))C(O) alkyl, —N(R^(p))CO₂alkyl, —N(R^(o))SO₂alkyl, —C(O)alkyl,—CO₂H, —CO₂alkyl, —CONR^(o)R^(p), —SO₂alkyl, or —SO₂NR^(o)R^(p); whereinR^(o) and R^(p) are independently for each occurrence H or alkyl; and

X, X′, Z, A, E, n, R¹ and R² are as defined herein.

In certain such embodiments, the compound of formula (V) can berepresented by formula (Va),

or a pharmaceutically acceptable salt thereof. In certain suchembodiments, X and X′ are both F.

In certain embodiments, the compound of Formula (I), (Ia), (Ib), (II),(IIa), (III), (IIIa), (IV), (IVa), (V), or (Va) is a compound selectedfrom those species described or exemplified in the detailed descriptionbelow.

In certain embodiments, this application provides a pharmaceuticalcomposition, comprising at least one compound of Formula (I), (Ia),(Ib), (II), (IIa), (III), (IIIa), (IV), (IVa), (V), or (Va), or apharmaceutically acceptable salt thereof. Pharmaceutical compositions asdescribed herein may further comprise a pharmaceutically acceptableexcipient. In certain embodiments, this application also describes acompound of Formula (I), (Ia), (Ib), (II), (IIa), (III), (IIIa), (IV),(IVa), (V), or (Va) or a pharmaceutically acceptable salt thereof, or acomposition comprising of any of the foregoing for use as a medicament.

In another aspect, this application provides methods of treating adisease, disorder, or medical condition mediated by orexin receptoractivity a subject in need of such treatment, such as those describedherein, comprising administering to the subject, such as a patient, aneffective amount of at least one compound described herein or apharmaceutically acceptable salt thereof in a dose, at a frequency, andfor a duration to provide a beneficial effect to the subject. The orexinreceptor can be OX₁, OX₂, or both.

In some embodiments, this application provides methods of treating adisease, disorder, or medical condition in a subject in need, such as apatient, comprising administering to the subject, such as a patient, aneffective amount of at least one compound described herein or apharmaceutically acceptable salt thereof in a dose, at a frequency, andfor a duration to provide a beneficial effect to the subject.

In certain embodiments, this application provides the use of a compounddescribed herein, or a pharmaceutically acceptable salt thereof, or acomposition comprising of any of the foregoing in the preparation of amedicament for the treatment of diseases, disorders, and medicalconditions regulated by orexin receptor activity, and the use of suchcompounds and salts for treatment of such diseases and medicalconditions.

In certain embodiments, this application provides the use of a compounddescribed herein, or a pharmaceutically acceptable salt thereof, or acomposition comprising of any of the foregoing in the preparation of amedicament for the treatment of diseases, disorders, and medicalconditions, and the use of such compounds and salts for treatment ofsuch diseases, disorder, and medical conditions.

In certain embodiments, this application provides a method of treating adisease, disorder, or medical condition in a subject, such as a patient,comprising modulating an orexin receptor, wherein the modulating anorexin receptor comprises administering to the subject at least onecompound of Formula (I), (Ia), (Ib), (II), (IIa), (III), (IIIa), (IV),(IVa), (V), or (Va) or a pharmaceutically acceptable salt thereof, or acomposition comprising of any of the foregoing, in a dose, at afrequency, and for a duration to provide a beneficial effect to thesubject patient.

In certain embodiments, the disease, disorder, or medical condition isan eating disorder, obesity, alcoholism or an alcohol-related disorder,drug abuse or addiction, a sleep disorder, a cognitive dysfunction in apsychiatric or neurologic disorder, depression, anxiety, panic disorder,schizophrenia, Alzheimer's disease, Parkinson's disease, Huntington'schorea, head ache, migraine, pain, gastrointestinal diseases, epilepsy,inflammations, immune-related diseases, ulcers, irritable bowelsyndrome, diarrhea, gastroesophageal reflux, endocrine-related diseases,cancer, hypertension, behavior disorder, mood disorder, manicdepression, dementia, sex disorder, psychosexual disorder, and renaldisease. In certain embodiments, the disease, disorder, or medicalcondition is selected from the group consisting of drug abuse oraddiction, a sleep disorder, a cognitive dysfunction in a psychiatric orneurologic disorder, depression, anxiety, panic disorder, post-traumaticstress disorder, seasonal affective disorder, schizophrenia, Alzheimer'sdisease, Parkinson's disease, Huntington's chorea, pain, behaviordisorder, mood disorder, manic depression, dementia, sex disorder, andpsychosexual disorder. In certain embodiments, the disease, disorder, ormedical condition is selected from the group consisting of an eatingdisorder, obesity, alcoholism or an alcohol-related disorder, headache,migraine, gastrointestinal diseases, inflammations, immune-relateddiseases, ulcers, irritable bowel syndrome, diarrhea, gastroesophagealreflux, endocrine-related diseases, cancer, hypertension, and renaldisease.

In certain embodiments, drug abuse and addiction can include abuse of oraddiction to cocaine, opiates, amphetamines, ethanol,cannabis/marijuana, or nicotine.

In certain embodiments, this application provides a method of modulatingthe activity of an orexin receptor, such as one or both of OX₁ or OX₂,comprising contacting a cell comprising the orexin receptor with aneffective amount of at least one compound described herein, or apharmaceutically acceptable salt thereof, or a composition comprisingany one of the foregoing.

In certain embodiments, this application describes a method ofmodulating the activity of an orexin receptor, such as one or both ofOX₁ or OX₂, comprising contacting a cell comprising the orexin receptorwith an effective amount of at least one compound of Formula (I), (Ia),(Ib), (II), (IIa), (III), (IIIa), (IV), (IVa), (V), or (Va) or apharmaceutically acceptable salt thereof, and/or with at least onecompound or pharmaceutical composition as described herein. In certainembodiments of the foregoing, the contacting is in vitro, ex vivo, or invivo.

Additional embodiments, features, and advantages of the invention willbe apparent from the following detailed description and through practiceof the embodiments described in this application.

DETAILED DESCRIPTION

The present application provides a compound of formula (I),

or a pharmaceutically acceptable salt thereof, wherein:

X is halogen, such as F;

X′ is H or halogen, such as F;

Z is NR² or O;

A is optionally substituted aryl, aroyl, heteroaryl, or heteroaroyl;

B is optionally substituted aryl or heteroaryl;

E is optionally substituted aryl or heteroaryl;

n is 1, 2, or 3;

R¹ is alkyl, such as C₁₋₄alkyl (e.g., methyl); and

R² is H or alkyl, such as C₁₋₄alkyl (e.g., methyl).

In certain embodiments, the compound of formula (I) can be representedby Formula (Ia):

or a pharmaceutically acceptable salt thereof, wherein

X is halogen, such as F;

X′ is H or halogen, such as F;

Z is NR² or O;

A is optionally substituted aryl, aroyl, heteroaryl, or heteroaroyl;

B is optionally substituted aryl or heteroaryl;

E is optionally substituted aryl or heteroaryl;

n=1, 2, or 3;

R¹ is alkyl, such as C₁₋₄alkyl (e.g., methyl); and

R² is H or alkyl, such as C₁₋₄alkyl (e.g., methyl).

In certain embodiments, the compound of formula (I) can be representedby formula (Ib),

or a pharmaceutically acceptable salt thereof, wherein

Z is NR² or O;

A is optionally substituted aryl, aroyl, heteroaryl, or heteroaroyl;

B is optionally substituted aryl or heteroaryl;

E is optionally substituted aryl or heteroaryl;

n is 1, 2, or 3;

R¹ is alkyl, such as C₁₋₄alkyl (e.g., methyl); and

R² is H or alkyl, such as C₁₋₄alkyl (e.g., methyl).

In certain embodiments of the compound of formula (I), (Ia), or (Ib), Ais optionally substituted with one or more substituents independentlyselected from the group consisting of alkyl, such as C₁₋₄alkyl (e.g.,methyl, ethyl, —CHF₂, or —CF₃); cycloalkyl; halo, such as —F, —Cl, or—Br (e.g., —Cl); —OH; alkoxy, such as methoxy; —CN; —NR^(a)R^(b);—N(R^(a))C(O) alkyl; —N(R^(a))CO₂alkyl; —N(R^(a))SO₂alkyl; —C(O)alkyl;—CO₂H; —CO₂alkyl; —CONR^(a)R^(b); —SO₂alkyl; and —SO₂NR^(a)R^(b);wherein R^(a) and R^(b) are independently for each occurrence H oralkyl. In certain such embodiments, A is aryl or heteroaryl.

In certain embodiments of the compound of formula (I), (Ia), or (Ib), Bis optionally substituted with one or more substituents independentlyselected from the group consisting of alkyl, such as C₁₋₄alkyl, (e.g.,methyl, ethyl, isopropyl, —CH₂CF₃, —CHF₂, or —CF₃); cycloalkyl; halo,such as —F, —Cl, or —Br (e.g., —F or —Cl); —OH; alkoxy, such as methoxyor isopropoxy (e.g., methoxy); —CN; —NR^(c)R^(d); —N(R^(c))C(O) alkyl;—N(R^(c))CO₂alkyl; —N(R^(c))SO₂alkyl; —C(O)alkyl; —CO₂H; —CO₂alkyl;—CONR^(c)R^(d); —SO₂alkyl; and —SO₂NR^(c)R^(d); wherein R^(c) and R^(d)are independently for each occurrence H or alkyl.

In certain embodiments of the compound of formula (I), (Ia), or (Ib), Eis optionally substituted with one or more substituents independentlyselected from the group consisting of alkyl, such as C₁₋₄alkyl (e.g.,methyl, ethyl, —CHF₂, or —CF₃); cycloalkyl; halo, such as —F, —Cl, or—Br (e.g., —F or —Cl); —OH; alkoxy, such as methoxy; —CN; —NR^(e)R^(f);—N(R^(e))C(O) alkyl; —N(R^(e))CO₂alkyl; —N(R^(e))SO₂alkyl; —C(O)alkyl;—CO₂H; —CO₂alkyl; —CONR^(e)R^(f); —SO₂alkyl; and —SO₂NR^(e)R^(f);wherein R^(e) and R^(f) are independently for each occurrence H oralkyl.

In certain embodiments, the compound of formula (I) can be representedby formula (II) or (IIa):

or a pharmaceutically acceptable salt thereof; wherein:

X is halogen, such as F;

X′ is H or halogen, such as F;

Z is NR² or O;

M is 1, 2, or 3;

B is aryl or heteroaryl, wherein B is optionally substituted with one ormore substituents independently selected from the group consisting ofalkyl, such as C₁₋₄alkyl (e.g., methyl, ethyl, isopropyl, —CH₂CF₃,—CHF₂, or —CF₃); cycloalkyl; halo, such as —F, —Cl, or —Br (e.g., —F or—Cl); —OH; alkoxy, such as methoxy or isopropoxy (e.g., methoxy); —CN;—NR^(c)R^(d); —N(R^(c))C(O) alkyl; —N(R^(c))CO₂alkyl; —N(R^(c))SO₂alkyl;—C(O)alkyl; —CO₂H; —CO₂alkyl; —CONR^(c)R^(d); —SO₂alkyl; and—SO₂NR^(c)R^(d); wherein R^(c) and R^(d) are independently for eachoccurrence H or alkyl;

E is aryl or heteroaryl, wherein E is optionally substituted with one ormore substituents independently selected from the group consisting ofalkyl, such as C₁₋₄alkyl (e.g., methyl, ethyl, —CHF₂, or —CF₃);cycloalkyl; halo, such as —F, —Cl, or —Br (e.g., —F or —Cl); —OH;alkoxy, such as methoxy; —CN; —NR^(e)R^(f); —N(R^(e))C(O) alkyl;—N(R^(e))CO₂alkyl; —N(R^(e))SO₂alkyl; —C(O)alkyl; —CO₂H; —CO₂alkyl;—CONR^(e)R^(f); —SO₂alkyl; and —SO₂NR^(e)R^(f); wherein R^(e) and R^(f)are independently for each occurrence H or alkyl;

n is 1, 2, or 3;

R¹ is alkyl, such as C₁₋₄alkyl (e.g., methyl);

R² is H or alkyl, such as C₁₋₄alkyl (e.g., methyl); and

R⁵ represents alkyl, cycloalkyl, halo, —OH, alkoxy, —CN, —NR^(j)R^(k),—N(R^(j))C(O) alkyl, —N(R^(j))CO₂alkyl, —N(R^(j))SO₂alkyl, —C(O)alkyl,—CO₂H, —CO₂alkyl, —CONR^(j)R^(k), —SO₂alkyl, or —SO₂NR^(j)R^(k); whereinR^(j) and R^(k) are independently for each occurrence H or alkyl.

In certain embodiments, the compound of formula (I) can be representedby formula (III) or (IIIa):

or a pharmaceutically acceptable salt thereof; wherein:

X is halogen, such as F;

X′ is H or halogen, such as F;

Z is NR² or O;

m is 1, 2, 3, or 4;

B is aryl or heteroaryl, wherein B is optionally substituted with one ormore substituents independently selected from the group consisting ofalkyl, such as C₁₋₄alkyl (e.g., methyl, ethyl, isopropyl, —CH₂CF₃,—CHF₂, or —CF₃); cycloalkyl; halo, such as —F, —Cl, or —Br (e.g., —F or—Cl); —OH; alkoxy, such as methoxy or isopropoxy (e.g., methoxy); —CN;—NR^(c)R^(d); —N(R^(c))C(O) alkyl; —N(R^(c))CO₂alkyl; —N(R^(c))SO₂alkyl;—C(O)alkyl; —CO₂H; —CO₂alkyl; —CONR^(c)R^(d); —SO₂alkyl; and—SO₂NR^(c)R^(d); wherein R^(c) and R^(d) are independently for eachoccurrence H or alkyl;

E is aryl or heteroaryl, wherein E is optionally substituted with one ormore substituents independently selected from the group consisting ofalkyl, such as C₁₋₄alkyl (e.g., methyl, ethyl, —CHF₂, or —CF₃);cycloalkyl; halo, such as —F, —Cl, or —Br (e.g., —F or —Cl); —OH;alkoxy, such as methoxy; —CN; —NR^(e)R^(f); —N(R^(e))C(O) alkyl;—N(R^(e))CO₂alkyl; —N(R^(e))SO₂alkyl; —C(O)alkyl; —CO₂H; —CO₂alkyl;—CONR^(e)R^(f); —SO₂alkyl; and —SO₂NR^(e)R^(f); wherein R^(e) and R^(f)are independently for each occurrence H or alkyl;

n is 1, 2, or 3;

R¹ is alkyl, such as C₁₋₄alkyl (e.g., methyl);

R² is H or alkyl, such as C₁₋₄alkyl (e.g., methyl); and

R⁵ represents alkyl, cycloalkyl, halo, —OH, alkoxy, —CN, —NR^(j)R^(k),—N(R^(j))C(O) alkyl, —N(R^(j))CO₂alkyl, —N(R^(j))SO₂alkyl, —C(O)alkyl,—CO₂H, —CO₂alkyl, —CONR^(j)R^(k), —SO₂alkyl, or —SO₂NR^(j)R^(k); whereinR^(j) and R^(k) are independently for each occurrence H or alkyl.

In certain embodiments, the compound of formula (I) can be representedby formula (IV) or (IVa):

or a pharmaceutically acceptable salt thereof, wherein:

X is halogen, such as F;

X′ is H or halogen, such as F;

Z is NR² or O;

A is aryl, aroyl, heteroaryl, or heteroaroyl, wherein A is optionallysubstituted with one or more substituents independently selected fromthe group consisting of alkyl, such as C₁₋₄alkyl (e.g., methyl, ethyl,—CHF₂, or —CF₃); cycloalkyl; halo, such as —F, —Cl, or —Br (e.g., —Cl);—OH; alkoxy, such as methoxy; —CN; —NR^(a)R^(b); —N(R^(a))C(O) alkyl;—N(R^(a))CO₂alkyl; —N(R^(a))SO₂alkyl; —C(O)alkyl; —CO₂H; —CO₂alkyl;—CONR^(a)R^(b); —SO₂alkyl; and —SO₂NR^(a)R^(b); wherein R^(a) and R^(b)are independently for each occurrence H or alkyl;

E is aryl or heteroaryl, wherein E is optionally substituted with one ormore substituents independently selected from the group consisting ofalkyl, such as C₁₋₄alkyl (e.g., methyl, ethyl, —CHF₂, or —CF₃);cycloalkyl; halo, such as —F, —Cl, or —Br (e.g., —F or —Cl); —OH;alkoxy, such as methoxy; —CN; —NR^(e)R^(f); —N(R^(e))C(O) alkyl;—N(R^(e))CO₂alkyl; —N(R^(e))SO₂alkyl; —C(O)alkyl; —CO₂H; —CO₂alkyl;—CONR^(e)R^(f); —SO₂alkyl; and —SO₂NR^(e)R^(f); wherein R^(e) and R^(f)are independently for each occurrence H or alkyl;

n is 1, 2, or 3;

R¹ is alkyl, such as C₁₋₄alkyl (e.g., methyl);

R² is H or alkyl, such as C₁₋₄alkyl (e.g., methyl);

R⁶ represents alkyl, cycloalkyl, halo, —OH, alkoxy, —CN, —NR^(o)R^(p),—N(R^(o))C(O) alkyl, —N(R^(p))CO₂alkyl, —N(R^(o))SO₂alkyl, —C(O)alkyl,—CO₂H, —CO₂alkyl, —CONR^(o)R^(p), —SO₂alkyl, or —SO₂NR^(o)R^(p); whereinR^(o) and R^(p) are independently for each occurrence H or alkyl.

In certain embodiments, the compound of formula (I) can be representedby formula (V) or (Va):

or a pharmaceutically acceptable salt thereof; wherein:

X is halogen, such as F;

X′ is H or halogen, such as F;

Z is NR² or O;

A is aryl, aroyl, heteroaryl, or heteroaroyl, wherein A is optionallysubstituted with one or more substituents independently selected fromthe group consisting of alkyl, such as C₁₋₄alkyl (e.g., methyl, ethyl,—CHF₂, or —CF₃); cycloalkyl; halo, such as —F, —Cl, or —Br (e.g., —Cl);—OH; alkoxy, such as methoxy; —CN; —NR^(a)R^(b); —N(R^(a))C(O) alkyl;—N(R^(a))CO₂alkyl; —N(R^(a))SO₂alkyl; —C(O)alkyl; —CO₂H; —CO₂alkyl;—CONR^(a)R^(b); —SO₂alkyl; and —SO₂NR^(a)R^(b); wherein R^(a) and R^(b)are independently for each occurrence H or alkyl;

E is aryl or heteroaryl, wherein E is optionally substituted with one ormore substituents independently selected from the group consisting ofalkyl, such as C₁₋₄alkyl (e.g., methyl, ethyl, —CHF₂, or —CF₃);cycloalkyl; halo, such as —F, —Cl, or —Br (e.g., —F or —Cl); —OH;alkoxy, such as methoxy; —CN; —NR^(e)R^(f); —N(R^(e))C(O) alkyl;—N(R^(e))CO₂alkyl; —N(R^(e))SO₂alkyl; —C(O)alkyl; —CO₂H; —CO₂alkyl;—CONR^(e)R^(f); —SO₂alkyl; and —SO₂NR^(e)R^(f); wherein R^(e) and R^(f)are independently for each occurrence H or alkyl;

n is 1, 2, or 3;

R¹ is alkyl, such as C₁₋₄alkyl (e.g., methyl);

R² is H or alkyl, such as C₁₋₄alkyl (e.g., methyl); and

R⁶ represents alkyl, cycloalkyl, halo, —OH, alkoxy, —CN, —NR^(o)R^(p),—N(R^(o))C(O) alkyl, —N(R^(p))CO₂alkyl, —N(R^(o))SO₂alkyl, —C(O)alkyl,—CO₂H, —CO₂alkyl, —CONR^(o)R^(p), —SO₂alkyl, or —SO₂NR^(o)R^(p); whereinR^(o) and R^(p) are independently for each occurrence H or alkyl.

In certain embodiments, compounds of formula (I), (Ia), (Ib), (II),(IIa), (III), (IIIa), (IV), (IVa), (V), or (Va), or pharmaceuticallyacceptable salts thereof, are further characterized as follows.

In certain embodiments, A is aryl or heteroaryl.

In certain embodiments, n is 1.

In certain embodiments, X′ is halogen, such as F.

In certain embodiments, Z is NR².

In certain embodiments, R² is hydrogen.

In certain other embodiments, R² is methyl.

In certain embodiments, each occurrence of X is —F.

In certain embodiments, R¹ is C₁₋₄alkyl, such as methyl.

In certain embodiments, A is an optionally substituted monocyclic orbicyclic heteroaryl.

In certain such embodiments, A is selected from the list consisting ofpyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, and benzoxazolyl. Incertain embodiments, A is pyridinyl. In certain embodiments, A ispyrimidinyl. In certain embodiments, A is pyrazinyl. In certainembodiments, A is pyridazinyl.

In certain embodiments, A is unsubstituted. In other embodiments, A isoptionally substituted with one or more alkyl, such as ethyl, —CHF₂, or—CF₃; alkoxy, such as methoxy; or halo, such as —Cl. In certain suchembodiments, A is optionally substituted with one or more substituentsindependently selected from the list consisting of —F, —Br, —Cl, —CHF₂,—CF₃, methyl, ethyl, and methoxy. In other embodiments, A is optionallysubstituted with one or more substituents independently selected fromthe list consisting of —F, —Br, —Cl, —CF₃, methyl, ethyl, and methoxy.

In certain embodiments, A is monosubstituted. In certain suchembodiments, A is substituted with —CHF₂ or —CF₃, such as —CF₃.

In certain embodiments, B is an optionally substituted aryl, such asphenyl.

In certain embodiments, B is an optionally substituted monocyclicheteroaryl or bicyclic heteroaryl. In certain such embodiments, Bselected from the list consisting of pyridinyl, pyrimidinyl, pyrazinyl,pyridazinyl, oxazolyl, isoxazolyl, imidazolyl, triazolyl, thiazolyl,thiophenyl, pyrazolyl, and benzoimidazolyl, such as pyridinyl,thiophenyl, oxazolyl, thiazolyl, pyrazolyl, triazolyl orbenzoimidazolyl. In certain embodiments, B is pyridinyl. In certainembodiments, B is thiophenyl. In certain embodiments, B is oxazolyl. Incertain embodiments, B is thiazolyl. In certain embodiments, B ispyrazolyl. In certain embodiments, B is triazolyl. In certainembodiments, B is benzoimidazolyl.

In certain embodiments, B is optionally substituted with one or moresubstituents independently selected from the group consisting of analkyl, such as methyl, ethyl, isopropyl, —CHF₂, —CF₃, or —CH₂CF₃; halo,such as —F or —Cl; alkoxy, such as methoxy; and —CN. In certainembodiments, B is optionally substituted with one or more substituentsindependently selected from the list consisting of —F, —Cl, —Br, —CN,methyl, ethyl, isopropyl, —CF₃, —CHF₂, —CH₂CF₃, isopropoxy, and methoxy.In other embodiments, B is optionally substituted with one or moresubstituents independently selected from the list consisting of —F, —Cl,—Br, —CN, methyl, ethyl, isopropyl, —CF₃, —CH₂CF₃, isopropoxy, andmethoxy. In certain such embodiments, B is optionally substituted withone or more alkyl, such as methyl.

In certain embodiments, B is monosubstituted. In certain suchembodiments, B is substituted with an alkyl, such as methyl.

In certain embodiments, E is an optionally substituted phenyl.

In certain embodiments, E is an optionally substituted monocyclicheteroaryl, such as triazoyl, tetrazolyl, pyrazolyl, pyridinyl,oxadiazolyl, pyrazinyl, or pyrimidinyl. In certain embodiments, E istriazoyl. In certain embodiments, E is tetrazolyl. In certainembodiments, E is pyrazolyl. In certain embodiments, E is pyridinyl. Incertain embodiments, E is oxadiazolyl. In certain embodiments, E ispyrimidinyl. In certain embodiments, E is pyrazinyl.

In certain embodiments, E is optionally substituted with one or moresubstituents independently selected from the group consisting of alkyl,such as methyl, ethyl, —CHF₂, or —CF₃, e.g., methyl, halo, such as —F,—Br, or —Cl, e.g., —F or —Cl; and alkoxy, such as methoxy. In otherembodiments, E is optionally substituted with one or more substituentsindependently selected from the group consisting of alkyl, such asmethyl, ethyl, or —CF₃, e.g., methyl, halo, such as —F, —Br, or —Cl,e.g., —F or —Cl; and alkoxy, such as methoxy. In further suchembodiments, E is optionally substituted with one or more substituentindependently selected from methyl or —F.

In certain embodiments, E is monosubstituted. In other embodiments, E isunsubstituted.

In certain embodiments, the fragment -B-E in the compound of formula(I), (Ia), (Ib), (II), (IIa), (III), or (IIIa) can be represented by

wherein:

Y, independently for each occurrence, represents CH or N; and

R³ represents alkyl, such as C₁₋₄alkyl(e.g., methyl, ethyl, isopropyl,—CH₂CF₃, or —CF₃); cycloalkyl; halo, such as —F, —Cl, or —Br (e.g., —For —Cl); —OH; alkoxy, such as methoxy or isopropoxy (e.g., methoxy);—CN; —NR^(g)R^(h); —N(R^(g))C(O) alkyl; —N(R^(g))CO₂alkyl;—N(R^(g))SO₂alkyl; —C(O)alkyl; —CO₂H; —CO₂alkyl; —CONR^(g)R^(h);—SO₂alkyl; or —SO₂NR^(g)R^(h); wherein R^(g) and R^(h) are eachindependently for each occurrence H or alkyl.

In certain such embodiments, the structure

is selected from the following:

For example, in certain embodiments, the fragment -B-E is

In certain such embodiments, R³ is alkyl, such as —CH₃ or —CF₃; oralkoxy, such as methoxy.

In other embodiments, the fragment -B-E is

In certain such embodiments, R³ is halo, such as —F or —Cl; or alkyl,such as methyl; or —CN.

In certain embodiments, the fragment -B-E in the compound of formula(I), (Ia), (Ib), (II), (IIa), (III), or (IIIa) forms a hetero-aromaticring structure of

wherein:

, independently for each occurrence, represents a single or double bond;

W, independently for each occurrence, represents N, S, O, or CH;

V represents N or C; and

R⁴ represents alkyl, such as C₁₋₄alkyl(e.g., methyl, ethyl, isopropyl,—CH₂CF₃, or —CF₃); cycloalkyl; halo, such as —F, —Cl, or —Br (e.g., —For —Cl); —OH; alkoxy, such as methoxy or isopropoxy (e.g., methoxy);—CN; —NR^(i)R^(j), —N(R^(i))C(O) alkyl, —N(R^(i))CO₂alkyl,—N(R^(i))SO₂alkyl, —C(O)alkyl, —CO₂H, —CO₂alkyl, —CONR^(i)R^(j),—SO₂alkyl, or —SO₂NR^(i)R^(j); wherein R^(i) and R^(j) are independentlyfor each occurrence H or alkyl.

In certain such embodiments, the structure

is selected from the following:

In certain embodiments, the structure

is

In certain such embodiments, R⁴ is C₁₋₄alkyl, such as methyl. In certainother embodiments, the structure

is

In certain such embodiments, R⁴ is C₁₋₄alkyl, such as methyl.

In certain embodiments, Z is O. In other embodiments, Z is NR².

In certain embodiments, n=1.

In certain embodiments, the compound of formula (I) is selected from thecompounds provided in Table 1, and pharmaceutically acceptable saltsthereof.

TABLE 1 Halo-Substituted Piperidine Derivatives as Orexin AntagonistsCom- pound # Compound 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

32

33

34

35

36

37

38

39

40

41

42

43

44

45

46

47

48

49

50

51

52

53

54

55

56

57

58

59

60

61

62

63

64

65

66

67

68

69

70

71

72

73

74

75

76

77

78

79

80

81

82

83

84

85

86

87

88

89

90

91

92

93

94

95

96

97

98

99

102

103

104

105

106

107

108

109

110

111

112

113

114

115

116

117

118

119

120

121

122

123

124

125

126

127

128

129

130

131

132

133

134

135

136

137

138

139

140

141

142

143

144

145

146

147

148

149

150

151

152

153

154

155

156

157

158

159

160

161

162

163

164

165

166

167

168

169

170

171

172

173

174

175

176

177

178

179

180

181

182

183

184

185

186

187

188

189

190

191

192

193

194

195

196

197

198

199

200

201

202

203

204

205

206

207

208

209

210

211

212

213

214

215

216

217

218

219

220

221

222

223

224

225

226

227

228

229

230

231

232

233

234

235

236

237

238

239

240

241

242

243

244

245

246

247

248

249

250

251

252

253

254

255

256

257

258

259

260

261

262

263

264

265

266

267

268

269

In certain embodiments, this application relates to a pharmaceuticalcomposition comprising (a) a compound of formula (I), (Ia), (Ib), (II),(IIa), (III), (IIIa), (IV), (IVa), (V), or (Va), or a pharmaceuticallyacceptable salt thereof, and (b) a pharmaceutically acceptableexcipient.

In certain embodiments, this application relates to a compound offormula (I), (Ia), (Ib), (II), (IIa), (III), (IIIa), (IV), (IVa), (V),or (Va), or a pharmaceutically acceptable salt thereof, or apharmaceutical composition comprising any one of the foregoing, for useas a medicament.

In certain embodiments, this application relates to a method of treatinga disease, disorder, or medical condition mediated by orexin receptoractivity in a subject in need of such treatment, comprisingadministering to the subject an effective amount of at least onecompound according to formula (I), (Ia), (Ib), (II), (IIa), (III),(IIIa), (IV), (IVa), (V), or (Va), or a pharmaceutically acceptable saltthereof, or a pharmaceutical composition comprising any one of theforegoing.

In certain embodiments, this application relates to a method of treatinga disease, disorder, or medical condition in a subject in need of suchtreatment, comprising administering to the subject an effective amountof at least one compound according to formula (I), (Ia), (Ib), (II),(IIa), (III), (IIIa), (IV), (IVa), (V), or (Va), or a pharmaceuticallyacceptable salt thereof, or a pharmaceutical composition comprising anyone of the foregoing. In certain such embodiments, the disease, disorderor medical condition mediated by orexin receptor activity is eatingdisorder, obesity, alcoholism or an alcohol-related disorder, drug abuseor addiction, a sleep disorder, a cognitive dysfunction in a psychiatricor neurologic disorder, depression, anxiety, panic disorder,post-traumatic stress disorder, seasonal affective disorder,schizophrenia, Alzheimer's disease, Parkinson's disease, Huntington'schorea, headache, migraine, pain, gastrointestinal diseases, epilepsy,inflammations, immune-related diseases, ulcers, irritable bowelsyndrome, diarrhea, gastroesophageal reflux, endocrine-related diseases,cancer, hypertension, behavior disorder, mood disorder, manicdepression, dementia, sex disorder, psychosexual disorder, and renaldisease. In certain such embodiments, the drug abuse or addiction isselected from abuse of or addiction to cocaine, opiates, amphetamines,ethanol, cannabis/marijuana, or nicotine.

In certain embodiments, this application relates to the use of acompound of formula (I), (Ia), (Ib), (II), (IIa), (III), (IIIa), (IV),(IVa), (V), or (Va), or a pharmaceutically acceptable salt thereof, or apharmaceutical composition of any one of the foregoing, in thepreparation of a medicament for the treatment of diseases, disorders,and medical conditions regulated by orexin receptor activity, and theuse of such compounds for treatment of such diseases and medicalconditions.

In certain embodiments, this application relates to the use of acompound of formula (I), (Ia), (Ib), (II), (IIa), (III), (IIIa), (IV),(IVa), (V), or (Va), or a pharmaceutically acceptable salt thereof, or apharmaceutical composition of any one of the foregoing, in thepreparation of a medicament for the treatment of diseases, disorders,and medical conditions, and the use of such compounds for treatment ofsuch diseases, disorder, and medical conditions. In certain suchembodiments, the disease, disorder, or medical condition is an eatingdisorder, obesity, alcoholism or an alcohol-related disorder, drug abuseor addiction, a sleep disorder, a cognitive dysfunction in a psychiatricor neurologic disorder, depression, anxiety, panic disorder,post-traumatic stress disorder, seasonal affective disorder,schizophrenia, Alzheimer's disease, Parkinson's disease, Huntington'schorea, headache, migraine, pain, gastrointestinal diseases, epilepsy,inflammations, immune-related diseases, ulcers, irritable bowelsyndrome, diarrhea, gastroesophageal reflux, endocrine-related diseases,cancer, hypertension, behavior disorder, mood disorder, manicdepression, dementia, sex disorder, psychosexual disorder, and renaldisease. In certain such embodiments, the drug abuse or addiction isselected from abuse of or addiction to cocaine, opiates, amphetamines,ethanol, cannabis/marijuana, or nicotine. In certain such embodiments,the disease, disorder, or medical condition is selected from the groupconsisting of drug abuse or addiction, a sleep disorder, a cognitivedysfunction in a psychiatric or neurologic disorder, depression,anxiety, panic disorder, post-traumatic stress disorder, seasonalaffective disorder, schizophrenia, Alzheimer's disease, Parkinson'sdisease, Huntington's chorea, pain, behavior disorder, mood disorder,manic depression, dementia, sex disorder, and psychosexual disorder. Incertain embodiments, the disease, disorder, or medical condition isselected from the group consisting of an eating disorder, obesity,alcoholism or an alcohol-related disorder, headache, migraine,gastrointestinal diseases, inflammations, immune-related diseases,ulcers, irritable bowel syndrome, diarrhea, gastroesophageal reflux,endocrine-related diseases, cancer, hypertension, and renal disease.

As discussed above, there is a need in the field for compounds with morefavorable metabolic stability and half lives. Certain embodiments ofthis application provide compounds found to have such advantages.

In certain embodiments, this application relates to a method ofmodulating the activity of an orexin receptor OX₁, OX₂, or both,comprising contacting a cell comprising the orexin receptor with aneffective amount of at least one compound of formula (I), (Ia), (Ib),(II), (IIa), (III), (IIIa), (IV), (IVa), (V), or (Va), or apharmaceutically acceptable salt thereof, or a pharmaceuticalcomposition of any one of the foregoing. In certain such embodiments,the contacting is in vitro, ex vivo, or in vivo.

In certain embodiments, this application relates to a method of treatinga disease or disorder in a subject, (e.g., a patient) in need thereof,comprising administering a compound of formula (I), (Ia), (Ib), (II),(IIa), (III), (IIIa), (IV), (IVa), (V), or (Va), or a pharmaceuticallyacceptable salt thereof, or a pharmaceutical composition of any one ofthe foregoing, wherein the disease or disorder is selected from thegroup consisting of an eating disorder, obesity, alcoholism or analcohol-related disorder, drug abuse or addiction, a sleep disorder, acognitive dysfunction in a psychiatric or neurologic disorder,depression, anxiety, panic disorder, post-traumatic stress disorder,seasonal affective disorder, schizophrenia, Alzheimer's disease,Parkinson's disease, Huntington's chorea, headache, migraine, pain,gastrointestinal diseases, epilepsy, inflammations, immune-relateddiseases, ulcers, irritable bowel syndrome, diarrhea, gastroesophagealreflux, endocrine-related diseases, cancer, hypertension, behaviordisorder, mood disorder, manic depression, dementia, sex disorder,psychosexual disorder, and renal disease. In certain such embodiments,the disease, disorder, or medical condition is selected from the groupconsisting of drug abuse or addiction, a sleep disorder, a cognitivedysfunction in a psychiatric or neurologic disorder, depression,anxiety, panic disorder, post-traumatic stress disorder, seasonalaffective disorder, schizophrenia, Alzheimer's disease, Parkinson'sdisease, Huntington's chorea, pain, behavior disorder, mood disorder,manic depression, dementia, sex disorder, and psychosexual disorder. Incertain such embodiments, the disease, disorder, or medical condition isselected from the group consisting of an eating disorder, obesity,alcoholism or an alcohol-related disorder, headache, migraine,gastrointestinal diseases, inflammations, immune-related diseases,ulcers, irritable bowel syndrome, diarrhea, gastroesophageal reflux,endocrine-related diseases, cancer, hypertension, and renal disease.

In certain such embodiments, disease or disorder is selected from thegroup consisting of drug abuse or addiction, panic disorder, anxiety,post-traumatic stress disorder, pain, depression, seasonal affectivedisorder, an eating disorder, and hypertension. In certain suchembodiments, the drug abuse or addiction is selected from abuse of oraddiction to cocaine, opiates, amphetamines, ethanol,cannabis/marijuana, or nicotine.

Those skilled in the art will recognize that the species listed orillustrated herein are not exhaustive, and that additional specieswithin the scope of these defined terms may also be selected.

The application also includes pharmaceutically acceptable prodrugs,salts, solvates, such as hydrates, of the compounds represented byFormula (I), (Ia), (Ib), (II), (IIa), (III), (IIIa), (IV), (IVa), (V),or (Va), preferably of those described above and of the specificcompounds exemplified herein, and pharmaceutical compositions comprisingsuch prodrugs, salts, or solvates, such as hydrates, and methods ofusing such salts or hydrates.

The present application also relates to pharmaceutically activemetabolites of compounds described herein, and uses of such metabolitesin the methods of the application.

Definitions

The definitions set forth in this application are intended to clarifyterms used throughout this application.

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as is commonly understood by one of ordinary skillin the art to which this invention belongs. All patents, applications,published applications and other publications referred to herein areincorporated by reference in their entireties to disclose and describethe methods and/or materials in connection with which the publicationsare cited. If a definition set forth in this section is contrary to orotherwise inconsistent with a definition set forth in a patent,application, or other publication that is herein incorporated byreference, the definition set forth in this section prevails over thedefinition incorporated herein by reference. Although any methods andmaterials similar or equivalent to those described herein can also beused in the practice or testing of the embodiments in presentapplication, the preferred methods and materials are now described.

To provide a more concise description, some of the quantitativeexpressions given herein are not qualified with the term “about.” It isunderstood that, whether the term “about” is used explicitly or not,every quantity given herein is meant to refer to the actual given value,and it is also meant to refer to the approximation to such given valuethat would reasonably be inferred based on the ordinary skill in theart, including equivalents and approximations due to the experimentaland/or measurement conditions for such given value. Whenever a yield isgiven as a percentage, such yield refers to a mass of the entity forwhich the yield is given with respect to the maximum amount of the sameentity that could be obtained under the particular stoichiometricconditions. Concentrations that are given as percentages refer to massratios, unless indicated differently.

Except as otherwise noted, the methods and techniques of the presentembodiments are generally performed according to conventional methodswell known in the art and as described in various general and morespecific references that are cited and discussed throughout the presentspecification. See, e.g., Loudon, Organic Chemistry, Fourth Edition, NewYork: Oxford University Press, 2002, pp. 360-361, 1084-1085; Smith andMarch, March's Advanced Organic Chemistry: Reactions, Mechanisms, andStructure, Fifth Edition, Wiley-Interscience, 2001.

The nomenclature used herein to name the subject compounds isillustrated in the Examples herein. This nomenclature has generally beenderived using the commercially-available ChemBioDraw Ultra software(Cambridgesoft/Perkin Elmer), Version 12.0.

It is to be understood that the present description is not limited toparticular embodiments described, as such may, of course, vary. It isalso to be understood that the terminology used herein is for thepurpose of describing particular embodiments only, and is not intendedto be limiting, since the scope of the present application will belimited only by the appended claims.

It is appreciated that certain features of the application, which are,for clarity, described in the context of separate embodiments, may alsobe provided in combination in a single embodiment. Conversely, variousfeatures of the application, which are, for brevity, described in thecontext of a single embodiment, may also be provided separately or inany suitable subcombination. All combinations of the embodimentspertaining to the chemical groups represented by the variables arespecifically embraced by the present application and are disclosedherein just as if each and every combination was individually andexplicitly disclosed, to the extent that such combinations embracecompounds that are stable compounds (i.e., compounds that can beisolated, characterized, and tested for biological activity). Inaddition, all subcombinations of the chemical groups listed in theembodiments describing such variables are also specifically embraced bythe present application and are disclosed herein just as if each andevery such sub-combination of chemical groups was individually andexplicitly disclosed herein.

Any formula depicted herein is intended to represent a compound of thatstructural formula as well as certain variations or forms. For example,a formula given herein is intended to include a racemic form, or one ormore enantiomeric, diastereomeric, or geometric isomers, or tautomericforms, or a mixture thereof. Additionally, any formula given herein isintended to refer also to a solvate, such as a hydrate, solvate, orpolymorph of such a compound, or a mixture thereof. Any formula givenherein is intended to refer to amorphous and/or crystalline physicalforms of the compound. The compounds described herein may beanalytically pure, or a mixture in which the compound comprises at least50%, at least 70%, at least 80%, at least 90%, at least 95%, or at least98% by weight of the mixture.

In addition, where features or aspects of the embodiments of thisapplication are described in terms of Markush groups, those skilled inthe art will recognize that embodiments described herein is also therebydescribed in terms of any individual member or subgroup of members ofthe Markush group. For example, if X is described as selected from thegroup consisting of bromine, chlorine, and iodine, claims for X beingbromine and claims for X being bromine and chlorine are fully described.

The term “herein” refers to the entire application.

As used herein, the singular forms “a,” “an,” and “the” include pluralreferents unless the context clearly dictates otherwise. It is furthernoted that the claims may be drafted to exclude any optional element. Assuch, this statement is intended to serve as antecedent basis for use ofsuch exclusive terminology as “solely,” “only” and the like inconnection with the recitation of claim elements, or use of a “negative”limitation.

As used herein, the terms “including,” “containing,” and “comprising”are used in their open, non-limiting sense.

As used herein, “subject” (as in the subject of the treatment) refers toboth mammals and non-mammals. Mammals include, for example, humans;non-human primates, e.g. apes and monkeys; and non-primates, e.g. mice,rats, rabbits, dogs, cats, cattle, horses, sheep, and goats. Non-mammalsinclude, for example, worms, fish and birds. In some embodiments, thesubject is a human.

“Substantially” as the term is used herein refers to being completely oralmost completely; for example, a composition that is “substantiallyfree” of a component either has none of the component or contains such atrace amount that any relevant functional property of the composition isunaffected by the presence of the trace amount, or a compound is“substantially pure” is there are only negligible traces of impuritiespresent.

The term “acyl” is art-recognized and refers to a group represented bythe general formula hydrocarbylC(O)—, preferably alkylC(O)—.

The term “acylamino” is art-recognized and refers to an amino groupsubstituted with an acyl group and may be represented, for example, bythe formula hydrocarbylC(O)NH—.

The term “acyloxy” is art-recognized and refers to a group representedby the general formula hydrocarbylC(O)O—, preferably alkylC(O)O—.

The term “alkoxy” refers to an alkyl group, preferably a lower alkylgroup, having an oxygen attached thereto. Representative alkoxy groupsinclude methoxy, ethoxy, propoxy, tert-butoxy and the like.

The term “alkoxyalkyl” refers to an alkyl group substituted with analkoxy group and may be represented by the general formulaalkyl-O-alkyl.

The term “alkenyl”, as used herein, refers to an aliphatic groupcontaining at least one double bond and is intended to include both“unsubstituted alkenyls” and “substituted alkenyls”, the latter of whichrefers to alkenyl moieties having substituents replacing a hydrogen onone or more carbons of the alkenyl group. Such substituents may occur onone or more carbons that are included or not included in one or moredouble bonds. Moreover, such substituents include all those contemplatedfor alkyl groups, as discussed below, except where stability isprohibitive. For example, substitution of alkenyl groups by one or morealkyl, carbocyclyl, aryl, heterocyclyl, or heteroaryl groups iscontemplated.

The term “alkynyl”, as used herein, refers to an aliphatic groupcontaining at least one triple bond and is intended to include both“unsubstituted alkynyls” and “substituted alkynyls”, the latter of whichrefers to alkynyl moieties having substituents replacing one or morehydrogens on one or more carbons of the alkynyl group. Such substituentsmay occur on one or more carbons that are included or not included inone or more triple bonds. Moreover, such substituents include all thosecontemplated for alkyl groups, as discussed above, except wherestability is prohibitive. For example, substitution of alkynyl groups byone or more alkyl, carbocyclyl, aryl, heterocyclyl, or heteroaryl groupsis contemplated.

An “alkyl” group or “alkane” is a straight chained or branchednon-aromatic hydrocarbon which is completely saturated. Typically, astraight chained or branched alkyl group has from 1 to about 20 carbonatoms, such as from 1 to 12 carbon atoms, preferably from 1 to about 10,more preferably from 1 to 4, unless otherwise defined. Examples ofstraight chained and branched alkyl groups include methyl, ethyl,n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl,isopentyl, tert-pentyl, hexyl, isohexyl, pentyl and octyl. A C₁-C₆straight chained or branched alkyl group is also referred to as a “loweralkyl” group.

Moreover, the term “alkyl” (or “lower alkyl”) as used throughout thespecification, examples, and claims is intended to include both“unsubstituted alkyls” and “substituted alkyls”, the latter of whichrefers to alkyl moieties having substituents replacing a hydrogen ormore hydrogens on one or more carbons of the hydrocarbon backbone. Suchsubstituents, if not otherwise specified, can include, for example, ahalogen (such as F, Cl, Br, or I), a hydroxyl, a carbonyl (such as acarboxyl, an alkoxycarbonyl, a formyl, or an acyl), a thiocarbonyl (suchas a thioester, a thioacetate, or a thioformate), an alkoxyl, aphosphoryl, a phosphate, a phosphonate, a phosphinate, an amino, anamido, an amidine, an imine, a cyano, a nitro, an azido, a sulfhydryl,an alkylthio, a sulfate, a sulfonate, a sulfamoyl, a sulfonamido, asulfonyl, a heterocyclyl, an aralkyl, or an aromatic or heteroaromaticmoiety. It will be understood by those skilled in the art that themoieties substituted on the hydrocarbon chain can themselves besubstituted, if appropriate. For instance, the substituents of asubstituted alkyl may include substituted and unsubstituted forms ofamino, azido, imino, amido, phosphoryl (including phosphonate andphosphinate), sulfonyl (including sulfate, sulfonamido, sulfamoyl andsulfonate), and silyl groups, as well as ethers, alkylthios, carbonyls(including ketones, aldehydes, carboxylates, and esters), haloalkyls(such as —CF₃, —CHF₂, —CH₂F,), —CN, and the like. Exemplary substitutedalkyls are described below. Cycloalkyls can be further substituted withalkyls, alkenyls, alkoxys, alkylthios, aminoalkyls, carbonyl-substitutedalkyls, haloalkyls (such as —CF₃, —CHF₂, —CH₂F), —CN, and the like.

The term “(ATOM)_(i-j)” with j>i, when used in conjunction with achemical moiety, such as, acyl, acyloxy, alkyl, alkenyl, alkynyl, oralkoxy is meant to include groups that contain from i to j (including iand j) atoms. For example, the term “C_(x-y)alkyl” refers to substitutedor unsubstituted saturated hydrocarbon groups, including straight-chainalkyl and branched-chain alkyl groups that contain from x to y carbonsin the chain, including haloalkyl groups such as —CF₃, —CHF₂, —CH₂F, or2,2,2-trifluoroethyl, etc. C₀ alkyl refers to a hydrogen atom where thegroup is in a terminal position, a bond if internal. Similarly, forexample, C₃₋₆cycloalkyl refers to a cycloalkyl as defined herein thathas 3 to 6 carbon ring atoms. The terms “C_(2-y)alkenyl” and“C_(2-y)alkynyl” refer to substituted or unsubstituted unsaturatedaliphatic groups analogous in length and possible substitution to thealkyls described above, but that contain at least one double or triplebond respectively.

The term “alkylamino”, as used herein, refers to an amino groupsubstituted with at least one alkyl group.

The term “alkylthio”, as used herein, refers to a thiol groupsubstituted with an alkyl group and may be represented by the generalformula alkylS—.

The term “hydrocarbyl”, as used herein, refers to a group that is bondedthrough a carbon atom that does not have a ═O or ═S substituent, andtypically has at least one carbon-hydrogen bond and a primarily carbonbackbone, but may optionally include heteroatoms. Thus, groups likemethyl, ethoxyethyl, 2-pyridyl, and trifluoromethyl are considered to behydrocarbyl for the purposes of this application, but substituents suchas acetyl (which has a ═O substituent on the linking carbon) and ethoxy(which is linked through oxygen, not carbon) are not. Hydrocarbyl groupsinclude, but are not limited to aryl, heteroaryl, carbocycle,heterocyclyl, alkyl, alkenyl, alkynyl, and combinations thereof.

The terms “amine” and “amino” are art-recognized and refer to bothunsubstituted and substituted amines and salts thereof, e.g., a moietythat can be represented by

wherein each R³⁰ independently represents a hydrogen or a hydrocarbylgroup, or two R³⁰ are taken together with the N atom to which they areattached complete a heterocycle having from 4 to 8 atoms in the ringstructure.

The term “aminoalkyl”, as used herein, refers to an alkyl groupsubstituted with an amino group.

The term “amide”, as used herein, refers to a group:

wherein each R³⁰ independently represent a hydrogen or hydrocarbylgroup, or two R³⁰ are taken together with the N atom to which they areattached complete a heterocycle having from 4 to 8 atoms in the ringstructure.

The term “carbamate” is art-recognized and refers to a group

wherein R²⁹ and R³⁰ independently represent hydrogen or a hydrocarbylgroup, such as an alkyl group, or R²⁹ and R³⁰ taken together with theintervening atom(s) complete a heterocycle having from 4 to 8 atoms inthe ring structure.

The term “halogen,” or “halide” represents chlorine, fluorine, bromine,or iodine. The term “halo” represents fluoro, chloro, bromo, or iodo.

The term “haloalkyl”, as used herein, refers to an alkyl group with oneor more halo substituents, or one, two, or three halo substituents.Examples of haloalkyl groups include —CF₃, —CH₂F, —CHF₂, —CH₂Br,—CH₂CF₃, and —CH₂CH₂F.

The term “heteroatom”, as used herein, refers to an atom of any elementother than carbon or hydrogen. Exemplary heteroatoms include but are notlimited to nitrogen, oxygen, and sulfur.

The term “heteroalkyl”, as used herein, refers to a saturated orunsaturated chain of carbon atoms and at least one heteroatom, whereinno two heteroatoms are adjacent.

The term “aryl”, as used herein, includes substituted or unsubstitutedmonocyclic aromatic rings in which each atom of the ring is carbon.Preferably the ring is a 5- to 7-membered ring, more preferably a6-membered ring. The term “aryl” also includes polycyclic ring systemshaving two or more cyclic rings in which two or more carbons are commonto two adjoining rings wherein at least one of the rings is aromatic,e.g., the other cyclic rings can be cycloalkyls, cycloalkenyls,cycloalkynyls, aryls, heteroaryls, and/or heterocyclyls. Aryl groupsinclude benzene, naphthalene, phenanthrene, phenol, aniline, and thelike.

The term “aralkyl”, as used herein, refers to an alkyl group substitutedwith an aryl group.

An “aroyl” group, as the term is used herein, refers to an aryl groupbonded via an exocyclic carbonyl group, such as a benzoyl group.

The term “heteroaryl”, as used herein, includes substituted orunsubstituted monocyclic aromatic ring system, preferably 5- to7-membered aromatic rings, more preferably 5- to 6-membered rings, whosering structures include at least one heteroatom, preferably one to fourheteroatoms, more preferably one to two heteroatoms. For example, a5-membered heteroaryl is furan, thiophene, pyrrole, oxazole, isoxazole,thiazole, isothiazole, pyrazole, imidazole, oxadiazole, thiadiazole,triazole, or tetrazole. In another example, a 6-membered heteroaryl ispyridine, pyrazine, pyrimidine, pyridazine, or triazine. The term“heteroaryl” also include substituted or unsubstituted “polycyclic” ringsystems having two or more cyclic rings in which two or more carbons arecommon to two adjoining rings wherein at least one of the rings isheteroaromatic, e.g., the other cyclic rings can be cycloalkyls,cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and/or heterocyclyls.

Illustrative examples of heteroaryl groups include but are not limitedto the following entities, in the form of properly bonded moieties:

The term “heteroaralkyl” or “hetaralkyl”, as used herein, refers to analkyl group substituted with a heteroaryl group.

A “heteroaroyl” group, as the term is used herein, refers to aheteroaryl group bonded via an exocyclic carbonyl group, analogous to abenzoyl group but wherein the phenyl ring of the benzoyl group isreplaced by a heteroaryl group.

The terms “heterocyclyl”, “heterocycle”, and “heterocyclic”, as usedherein, refer to substituted or unsubstituted non-aromatic ringstructures, preferably 3- to 10-membered rings, more preferably 3- to7-membered rings, whose ring structures include at least one heteroatom,preferably one to four heteroatoms, more preferably one or twoheteroatoms. The terms “heterocyclyl” and “heterocyclic” also includesubstituted or unsubstituted polycyclic ring systems having two or morecyclic rings in which two or more carbons are common to two adjoiningrings wherein at least one of the rings is heterocyclic, e.g., the othercyclic rings can be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls,heteroaryls, and/or heterocyclyls. Heterocyclyl groups include, forexample, piperidine, piperazine, pyrrolidine, morpholine, lactones,lactams, and the like.

The term “heterocyclylalkyl”, as used herein, refers to an alkyl groupsubstituted with a heterocycle group which is optionally substituted.

The terms “carbocycle”, and “carbocyclic”, as used herein, refers to asaturated or unsaturated ring in which each atom of the ring is carbon.The term carbocycle includes both aromatic carbocycles and non-aromaticcarbocycles. Non-aromatic carbocycles include both cycloalkane rings, inwhich all carbon atoms are saturated, and cycloalkene rings, whichcontain at least one double bond. “Carbocycle” includes 5-7 memberedmonocyclic and 8-12 membered bicyclic rings. Each ring of a bicycliccarbocycle may be selected from saturated, unsaturated and aromaticrings. Carbocycle includes bicyclic molecules in which one, two or threeor more atoms are shared between the two rings. The term “fusedcarbocycle” refers to a bicyclic carbocycle in which each of the ringsshares two adjacent atoms with the other ring. Each ring of a fusedcarbocycle may be selected from saturated, unsaturated and aromaticrings. In an exemplary embodiment, an aromatic ring, e.g., phenyl, maybe fused to a saturated or unsaturated ring, e.g., cyclohexane,cyclopentane, or cyclohexene. Any combination of saturated, unsaturatedand aromatic bicyclic rings, as valence permits, is included in thedefinition of carbocyclic. Exemplary “carbocycles” include cyclopentane,cyclohexane, bicyclo[2.2.1]heptane, 1,5-cyclooctadiene,1,2,3,4-tetrahydronaphthalene, bicyclo[4.2.0]oct-3-ene, naphthalene andadamantane. Exemplary fused carbocycles include decalin, naphthalene,1,2,3,4-tetrahydronaphthalene, bicyclo[4.2.0]octane,4,5,6,7-tetrahydro-1H-indene and bicyclo[4.1.0]hept-3-ene. “Carbocycles”may be substituted at any one or more positions capable of bearing ahydrogen atom.

A “cycloalkyl” group, as used herein, refers to a cyclic hydrocarbonwhich is completely saturated. “Cycloalkyl” includes monocyclic andbicyclic rings. Typically, a monocyclic cycloalkyl group has from 3 toabout 10 carbon atoms, more typically 3 to 8 carbon atoms unlessotherwise defined. The second ring of a bicyclic cycloalkyl may beselected from saturated, unsaturated and aromatic rings. Cycloalkylincludes bicyclic molecules in which one, two or three or more atoms areshared between the two rings. The term “fused cycloalkyl” refers to abicyclic cycloalkyl in which each of the rings shares two adjacent atomswith the other ring. The second ring of a fused bicyclic cycloalkyl maybe selected from saturated, unsaturated and aromatic rings.

The term “carbocyclylalkyl”, as used herein, refers to an alkyl groupsubstituted with a carbocycle group.

A “cycloalkenyl” group, as used herein, refers to a cyclic hydrocarboncontaining one or more double bonds. A “cycloalkynyl” group is a cyclichydrocarbon containing one or more triple bonds.

The terms “polycyclyl”, “polycycle”, and “polycyclic”, as used herein,refer to two or more rings (e.g., cycloalkyls, cycloalkenyls,cycloalkynyls, aryls, heteroaryls, and/or heterocyclyls) in which two ormore atoms are common to two adjoining rings, e.g., the rings are “fusedrings”. Each of the rings of the polycycle can be substituted orunsubstituted. In certain embodiments, each ring of the polycyclecontains from 3 to 10 atoms in the ring, preferably from 5 to 7.

The term “carbonate” is art-recognized and refers to a group —OCO₂—R³⁰,wherein R³⁰ represents a hydrocarbyl group.

The term “carboxy”, as used herein, refers to a group represented by theformula —CO₂H.

The term “ester”, as used herein, refers to a group —C(O)OR³⁰ whereinR³⁰ represents a hydrocarbyl group.

The term “ether,” as used herein, refers to a hydrocarbyl group linkedthrough an oxygen to another hydrocarbyl group. Accordingly, an ethersubstituent of a hydrocarbyl group may be hydrocarbyl-O—. Ethers may beeither symmetrical or unsymmetrical. Examples of ethers include, but arenot limited to, heterocycle-O-heterocycle and aryl-O-heterocycle. Ethersinclude “alkoxyalkyl” groups, which may be represented by the generalformula alkyl-O-alkyl.

The term “sulfate” is art-recognized and refers to the group —OSO₃H, ora pharmaceutically acceptable salt thereof.

The term “sulfonamide” is art-recognized and refers to the grouprepresented by the general formulae

wherein R²⁹ and R³⁰ independently represents hydrogen or hydrocarbyl,such as alkyl, or R²⁹ and R³⁰ taken together with the interveningatom(s) complete a heterocycle having from 4 to 8 atoms in the ringstructure.

The term “sulfoxide” is art-recognized and refers to the group—S(O)—R³⁰, wherein R³⁰ represents a hydrocarbyl.

The term “sulfonate” is art-recognized and refers to the group SO₃H, ora pharmaceutically acceptable salt thereof.

The term “sulfone” is art-recognized and refers to the group —S(O)₂—R³⁰,wherein R³⁰ represents a hydrocarbyl.

The term “thioalkyl”, as used herein, refers to an alkyl groupsubstituted with a thiol group.

The term “thioester”, as used herein, refers to a group —C(O)SR³⁰ or—SC(O)R³⁰ wherein R³⁰ represents a hydrocarbyl.

The term “thioether”, as used herein, is equivalent to an ether, whereinthe oxygen is replaced with a sulfur.

The term “urea” is art-recognized and may be represented by the generalformula

wherein R²⁹ and R³⁰ independently represent hydrogen or a hydrocarbyl,such as alkyl, or either occurrence of R²⁹ taken together with R³⁰ andthe intervening atom(s) complete a heterocycle having from 4 to 8 atomsin the ring structure.

The term “substituted”, as used herein, refers to moieties havingsubstituents replacing one or more hydrogens on one or more carbons ofthe backbone. It will be understood that “substitution” or “substitutedwith” includes the implicit proviso that such substitution is inaccordance with permitted valence of the substituted atom and thesubstituent, and that the substitution results in a stable compound,e.g., which does not spontaneously undergo transformation such as byrearrangement, cyclization, elimination, etc. As used herein, the term“substituted” is contemplated to include all permissible substituents oforganic compounds. In a broad aspect, the permissible substituentsinclude acyclic and cyclic, branched and unbranched, carbocyclic andheterocyclic, aromatic and non-aromatic substituents of organiccompounds. The permissible substituents can be one or more and the sameor different for appropriate organic compounds. For purposes of thisapplication, the heteroatoms such as nitrogen may have hydrogensubstituents and/or any permissible substituents of organic compoundsdescribed herein which satisfy the valences of the heteroatoms. In someembodiments, “substituted” means that the specified group or moietybears one, two, or three substituents. In other embodiments,“substituted” means that the specified group or moiety bears one or twosubstituents. In still other embodiments, “substituted” refers to thespecified group or moiety bears one substituent.

Substituents can include any substituents described herein, for example,a halogen, a hydroxyl, a carbonyl (such as a carboxyl, analkoxycarbonyl, a formyl, or an acyl), a thiocarbonyl (such as athioester, a thioacetate, or a thioformate), an alkoxyl, a phosphoryl, aphosphate, a phosphonate, a phosphinate, an amino, an amido, an amidine,an imine, a cyano, a nitro, an azido, a sulfhydryl, an alkylthio, asulfate, a sulfonate, a sulfamoyl, a sulfonamido, a sulfonyl, aheterocyclyl, an aralkyl, or an aromatic or heteroaromatic moiety. Itwill be understood by those skilled in the art that substituents canthemselves be substituted, if appropriate.

Unless specifically stated as “unsubstituted,” references to chemicalmoieties herein are understood to include substituted variants. Forexample, reference to an “aryl” group or moiety implicitly includes bothsubstituted and unsubstituted variants. The term “unsubstituted” refersto that the specified group bears no substituents.

The term “optionally substituted”, as used herein, means thatsubstitution is optional and therefore it is possible for the designatedatom or moiety to be unsubstituted.

Any disubstituent referred to herein is meant to encompass the variousattachment possibilities when more than one of such possibilities areallowed. For example, reference to disubstituent -A-B-, where A≠B,refers herein to such disubstituent with A attached to a firstsubstituted member and B attached to a second substituted member, and italso refers to such disubstituent with A attached to the secondsubstituted member and B attached to the first substituted member.

“Protecting group”, as used herein, refers to a group of atoms that,when attached to a reactive functional group in a molecule, mask, reduceor prevent the reactivity of the functional group. Typically, aprotecting group may be selectively removed as desired during the courseof a synthesis. Examples of protecting groups can be found in Greene andWuts, Protective Groups in Organic Chemistry, 3^(rd) Ed., 1999, JohnWiley & Sons, NY and Harrison et al., Compendium of Synthetic OrganicMethods, Vols. 1-8, 1971-1996, John Wiley & Sons, NY. Representativenitrogen protecting groups include, but are not limited to, formyl,acetyl, trifluoroacetyl, benzyl, benzyloxycarbonyl (“CBZ”),tert-butoxycarbonyl (“Boc”), trimethylsilyl (“TMS”),2-trimethylsilyl-ethanesulfonyl (“TES”), trityl and substituted tritylgroups, allyloxycarbonyl, 9-fluorenylmethyloxycarbonyl (“FMOC”),nitro-veratryloxycarbonyl (“NVOC”) and the like. Representativehydroxylprotecting groups include, but are not limited to, those wherethe hydroxyl group is either acylated (esterified) or alkylated such asbenzyl and trityl ethers, as well as alkyl ethers, tetrahydropyranylethers, trialkylsilyl ethers (e.g., TMS or TIPS groups), glycol ethers,such as ethylene glycol and propylene glycol derivatives and allylethers.

The term “pharmaceutically acceptable” is employed herein to refer tothose compounds, materials, compositions, and/or dosage forms which are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of human beings and animals without excessive toxicity,irritation, allergic response, or other problem or complication,commensurate with a reasonable benefit/risk ratio.

A “pharmaceutically acceptable salt” is intended to mean a salt of afree acid or base of a compound represented herein that is non-toxic,biologically tolerable, or otherwise biologically suitable foradministration to the subject. See, generally, S. M. Berge, et al.,“Pharmaceutical Salts,” J. Pharm. Sci., 1977, 66, 1-19. Preferredpharmaceutically acceptable salts are those that are pharmacologicallyeffective and suitable for contact with the tissues of subjects withoutundue toxicity, irritation, or allergic response. A compound describedherein may possess a sufficiently acidic group, a sufficiently basicgroup, both types of functional groups, or more than one of each type,and accordingly react with a number of inorganic or organic bases, andinorganic and organic acids, to form a pharmaceutically acceptable salt.

For a compound described herein that contains a basic group, such as anamine, a pharmaceutically acceptable salt may be prepared by anysuitable method available in the art, for example, treatment of the freebase with an inorganic acid, such as hydrochloric acid, hydrobromicacid, sulfuric acid, sulfamic acid, nitric acid, boric acid, phosphoricacid, and the like, or with an organic acid, such as acetic acid,phenylacetic acid, propionic acid, stearic acid, lactic acid, ascorbicacid, maleic acid, hydroxymaleic acid, isethionic acid, succinic acid,valeric acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid,glycolic acid, salicylic acid, oleic acid, palmitic acid, lauric acid, apyranosidyl acid, such as glucuronic acid or galacturonic acid, analpha-hydroxy acid, such as mandelic acid, citric acid, or tartaricacid, an amino acid, such as aspartic acid or glutamic acid, an aromaticacid, such as benzoic acid, 2-acetoxybenzoic acid, naphthoic acid, orcinnamic acid, a sulfonic acid, such as laurylsulfonic acid,p-toluenesulfonic acid, methanesulfonic acid, or ethanesulfonic acid, orany compatible mixture of acids such as those given as examples herein,and any other acid and mixture thereof that are regarded as equivalentsor acceptable substitutes in light of the ordinary level of skill inthis technology.

For a compound described herein that contains an acidic group, such as acarboxylic acid group, base addition salts can be prepared by anysuitable method available in the art, for example, treatment of suchcompound with a sufficient amount of the desired the desired base,either neat or in a suitable inert solvent. Examples of pharmaceuticallyacceptable base addition salts include, but are not limited to, lithium,sodium, potassium, calcium, ammonium, zinc, or magnesium salt, or othermetal salts; organic amino salts, such as, alkyl, dialkyl, trialkyl, ortetra-alkyl ammonium salts.

Other examples of pharmaceutically acceptable salts include, but are notlimited to, camsylate, sulfates, pyrosulfates, bisulfates, sulfites,bisulfites, phosphates, monohydrogen-phosphates, dihydrogenphosphates,metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates,propionates, decanoates, caprylates, acrylates, formates, isobutyrates,caproates, heptanoates, propiolates, oxalates, malonates, succinates,suberates, sebacates, fumarates, maleates, butyne-1,4-dioates,hexyne-1,6-dioates, benzoates, chlorobenzoates, methylbenzoates,dinitrobenzoates, hydroxybenzoates, methoxybenzoates, phthalates,sulfonates, methylsulfonates, propylsulfonates, besylates,xylenesulfonates, naphthalene-1-sulfonates, naphthalene-2-sulfonates,phenylacetates, phenylpropionates, phenylbutyrates, citrates, lactates,γ-hydroxybutyrates, glycolates, tartrates, and mandelates. Lists ofother suitable pharmaceutically acceptable salts are found inRemington's Pharmaceutical Sciences, 17^(th) Edition, Mack PublishingCompany, Easton, Pa., 1985.

The neutral forms of the compounds are preferably regenerated bycontacting the salt with a base or acid and isolating the parentcompound in the conventional manner. The parent form of the compounddiffers from the various salt forms in certain physical properties, suchas solubility in polar solvents, but otherwise the salts are equivalentto the parent form of the compound for the purposes of the presentapplication.

The term “prodrug” is intended to encompass compounds which, underphysiologic conditions, are converted into the therapeutically activeagents of the present application, e.g., a compound of described herein.A common method for making a prodrug is to include one or more selectedmoieties which are hydrolyzed under physiologic conditions to yield thedesired molecule. In certain embodiments, the prodrug is converted by anenzymatic activity of the host animal. For example, a prodrug with anitro group on an aromatic ring could be reduced by reductase togenerate the desired amino group of the corresponding active compound invivo. In another example, functional groups such as a hydroxyl,carbonate, or carboxylic acid in the parent compound are presented as anester, which could be cleaved by esterases. Additionally, amine groupsin the parent compounds are presented in, but not limited to, carbamate,N-alkylated or N-acylated forms (Simplicio et al, “Prodrugs for Amines,”Molecules, (2008), 13:519-547). In certain embodiments, some or all ofthe compounds of described herein in a formulation represented above canbe replaced with the corresponding suitable prodrug.

A “pharmaceutically acceptable prodrug” is a prodrug that is non-toxic,biologically tolerable, and otherwise biologically suitable foradministration to the subject. Illustrative procedures for the selectionand preparation of suitable prodrug derivatives are described, forexample, in “Design of Prodrugs”, ed. H. Bundgaard, Elsevier, 1985.

A “pharmaceutically active metabolite” or “metabolite” refers to apharmacologically active product of metabolism/biochemical modificationof a compound described herein, e.g., a compound of Formula (I), (Ia),or (Ib) or salt thereof, under physiological conditions, e.g., throughcertain enzymatic pathway. For example, an oxidative metabolite isformed by oxidation of the parent compound during metabolism, such asthe oxidation of a pyridine ring to pyridine-N-oxide. In anotherexample, an oxidative metabolite is formed by demethylation of a methoxygroup to result in a hydroxyl group.

Prodrugs and active metabolites of a compound may be determined usingroutine techniques known or available in the art. See, e.g., Bertoliniet al., J. Med. Chem. 1997, 40, 2011-2016; Shan et al., J. Pharm. Sci.1997, 86 (7), 765-767; Bagshawe, Drug Dev. Res. 1995, 34, 220-230;Bodor, Adv. Drug Res. 1984, 13, 255-331; Bundgaard, Design of Prodrugs(Elsevier Press, 1985); and Larsen, Design and Application of Prodrugs,Drug Design and Development (Krogsgaard-Larsen et al., eds., HarwoodAcademic Publishers, 1991).

Compounds of formulae (I), (Ia), (Ib), (II), (IIa), (III), (IIIa), (IV),(IVa), (V), and (Va), as disclosed herein, can also exist as various“solvates” or “hydrates.” A “hydrate” is a compound that exists in acomposition with water molecules. The composition can include water instoichiometric quantities, such as a monohydrate or a dihydrate, or caninclude water in random amounts. A “solvate” is a similar compositionexcept that a solvent other that water, such as with methanol, ethanol,dimethylformamide, diethyl ether and the like replaces the water. Forexample, methanol or ethanol can form an “alcoholate,”” which can againbe stoichiometic or non-stoichiometric. Mixtures of such solvates orhydrates can also be prepared. The source of such solvate or hydrate canbe from the solvent of crystallization, inherent in the solvent ofpreparation or crystallization, or adventitious to such solvent.

The compounds of the application, including their pharmaceuticallyacceptable salts and prodrugs, can exist as various polymorphs,pseudo-polymorphs, or in amorphous state. The term “polymorph”, as usedherein, refers to different crystalline forms of the same compound andother solid state molecular forms including pseudo-polymorphs, such ashydrates, solvates, or salts of the same compound. Different crystallinepolymorphs have different crystal structures due to a different packingof molecules in the lattice, as a result of changes in temperature,pressure, or variations in the crystallization process. Polymorphsdiffer from each other in their physical properties, such as x-raydiffraction characteristics, stability, melting points, solubility, orrates of dissolution in certain solvents. Thus crystalline polymorphicforms are important aspects in the development of suitable dosage formsin pharmaceutical industry.

The present application further embraces isolated compounds according toformula (I), (Ia), (Ib), (II), (IIa), (III), (IIIa), (IV), (IVa), (V),or (Va). The term “isolated compound” refers to a preparation of acompound of formula (I), (Ia), (Ib), (II), (IIa), (III), (IIIa), (IV),(IVa), (V), or (Va), or a mixture of compounds according to formula (I),(Ia), (Ib), (II), (IIa), (III), (IIIa), (IV), (IVa), (V), or (Va),wherein the isolated compound has been separated from the reagents used,and/or byproducts formed, in the synthesis of the compound or compounds.“Isolated” does not mean that the preparation is technically pure(homogeneous), but it is sufficiently pure to compound in a form inwhich it can be used therapeutically. Preferably an “isolated compound”refers to a preparation of a compound of formula (I), (Ia), (Ib), (II),(IIa), (III), (IIIa), (IV), (IVa), (V), or (Va) or a mixture ofcompounds according to formula (I), (Ia), (Ib), (II), (IIa), (III),(IIIa), (IV), (IVa), (V), or (Va), which contains the named compound ormixture of compounds according to formula (I), (Ia), (Ib), (II), (IIa),(III), (IIIa), (IV), (IVa), (V), or (Va) in an amount of at least 10percent by weight of the total weight. Preferably the preparationcontains the named compound or mixture of compounds in an amount of atleast 50% by weight of the total weight; more preferably at least 80% byweight of the total weight; and most preferably at least 90%, at least95% or at least 98% by weight of the total weight of the preparation.

The compounds of the application and intermediates may be isolated fromtheir reaction mixtures and purified by standard techniques such asfiltration, liquid-liquid extraction, solid phase extraction,distillation, recrystallization or chromatography, including flashcolumn chromatography, or HPLC.

Isomerism and Tautomerism in Described Compounds Tautomerism

Within the present application it is to be understood that a compounddescribed herein or a salt thereof may exhibit the phenomenon oftautomerism whereby two chemical compounds that are capable of facileinterconversion by exchanging a hydrogen atom between two atoms, toeither of which it forms a covalent bond. Since the tautomeric compoundsexist in mobile equilibrium with each other they may be regarded asdifferent isomeric forms of the same compound. It is to be understoodthat the formulae drawings within this specification can represent onlyone of the possible tautomeric forms. However, it is also to beunderstood that the application encompasses any tautomeric form, and isnot to be limited merely to any one tautomeric form utilized within theformulae drawings. The formulae drawings within this specification canrepresent only one of the possible tautomeric forms and it is to beunderstood that the specification encompasses all possible tautomericforms of the compounds drawn not just those forms which it has beenconvenient to show graphically herein. For example, tautomerism may beexhibited by a pyrazolyl group bonded as indicated by the wavy line.While both substituents would be termed a 4-pyrazolyl group, it isevident that a different nitrogen atom bears the hydrogen atom in eachstructure.

Such tautomerism can also occur with substituted pyrazoles such as3-methyl, 5-methyl, or 3,5-dimethylpyrazoles, and the like. Anotherexample of tautomerism is amido-imido (lactam-lactim when cyclic)tautomerism, such as is seen in heterocyclic compounds bearing a ringoxygen atom adjacent to a ring nitrogen atom. For example, theequilibrium:

is an example of tautomerism. Accordingly, a structure depicted hereinas one tautomer is intended to also include the other tautomer.

Optical Isomerism

It will be understood that when compounds of the present applicationcontain one or more chiral centers, the compounds may exist in, and maybe isolated as pure enantiomeric or diastereomeric forms or as racemicmixtures. The present application therefore includes any possibleenantiomers, diastereomers, racemates in their pure forms or mixturesthereof, and salts thereof, of the compounds of the application.

The isomers resulting from the presence of a chiral center comprise apair of non-superimposable isomers that are called “enantiomers.” Singleenantiomers of a pure compound are optically active, i.e., they arecapable of rotating the plane of plane polarized light. Singleenantiomers are designated according to the Cahn-Ingold-Prelog system.The priority of substituents is ranked based on atomic weights, a higheratomic weight, as determined by the systematic procedure, having ahigher priority ranking. Once the priority ranking of the four groups isdetermined, the molecule is oriented so that the lowest ranking group ispointed away from the viewer. Then, if the descending rank order of theother groups proceeds clockwise, the molecule is designated (R) and ifthe descending rank of the other groups proceeds counterclockwise, themolecule is designated (S). In the example in Scheme 14, theCahn-Ingold-Prelog ranking is A>B>C>D. The lowest ranking atom, D isoriented away from the viewer.

In certain embodiments, the therapeutic preparation may be enriched toprovide predominantly one enantiomer of a compound (e.g., of formula(I), (Ia), or (Ib)). An enantiomerically enriched mixture may comprise,for example, at least 60 mol percent of one enantiomer, or morepreferably at least 75, 90, 95, or even 99 mol percent. In certainembodiments, a compound of the invention may have greater than 30% ee,40% ee, 50% ee, 60% ee, 70% ee, 80% ee, 90% ee, or even 95% or greateree. In certain embodiments, the compound enriched in one enantiomer issubstantially free of the other enantiomer, wherein substantially freemeans that the substance in question makes up less than 10%, or lessthan 5%, or less than 4%, or less than 3%, or less than 2%, or less than1% as compared to the amount of the other enantiomer, e.g., in thecomposition or compound mixture. For example, if a composition orcompound mixture contains 98 grams of a first enantiomer and 2 grams ofa second enantiomer, it would be said to contain 98 mol percent of thefirst enantiomer and only 2% of the second enantiomer.

In certain embodiments, compounds of the application may have more thanone stereocenter. In certain such embodiments, compounds of theapplication may be enriched in one or more diastereomer. For example, acompound of the application may have greater than 30% de, 40% de, 50%de, 60% de, 70% de, 80% de, 90% de, or even 95% or greater de.

Isolated optical isomers may be purified from racemic mixtures bywell-known chiral separation techniques, such as but not limited to,normal and reverse phase chromatography, and crystallization. Accordingto one such method, a racemic mixture of a compound of the application,or a chiral intermediate thereof, is separated using a chiral salt orcarried out on a Chiralcell OD column. The column is operated accordingto the manufacturer's instructions.

Isolated optical isomers (enantiomerically pure compounds) can also beprepared by the use of chiral intermediates or catalysts in synthesis.When a chiral synthetic intermediate is used, the optical center (chiralcenter) can be preserved without racemization throughout the remainderof the preparative procedure, as is well known in the art. Chiralcatalyst can be used to impart at least some degree of enantiomericpurity to products of reactions catalyzed by the chiral catalyst. And,in some cases, compounds having at least some degree of enantiomericenrichment can be obtained by physical processes such as selectivecrystallization of salts or complexes formed with chiral adjuvants.

A variety of compounds in the present application may exist inparticular geometric or stereoisomeric forms. The present applicationtakes into account all such compounds, including tautomers, cis- andtrans-isomers, R- and S-enantiomers, diastereomers, (D)-isomers,(L)-isomers, the racemic mixtures thereof, and other mixtures thereof,as being covered within the scope of this application. All tautomericforms are encompassed in the present application. Additional asymmetriccarbon atoms may be present in a substituent such as an alkyl group. Allsuch isomers, as well as mixtures thereof, are intended to be includedin this application, unless the stereochemistry or isomeric form isspecifically indicated.

Rotational Isomerism

It is understood that due to chemical properties (i.e., resonancelending some double bond character to the C—N bond) of restrictedrotation about the amide bond linkage (as illustrated below) it ispossible to observe separate rotamer species and even, under somecircumstances, to isolate such species (see below). It is furtherunderstood that certain structural elements, including steric bulk orsubstituents on the amide nitrogen, may enhance the stability of arotamer to the extent that a compound may be isolated as, and existindefinitely, as a single stable rotamer. The present applicationtherefore includes any possible stable rotamers of formula (I) which arebiologically active in the treatment of cancer or other proliferativedisease states.

Regioisomerism

The preferred compounds of the present application have a particularspatial arrangement of substituents on the aromatic rings, which arerelated to the structure activity relationship demonstrated by thecompound class. Often such substitution arrangement is denoted by anumbering system; however, numbering systems are often not consistentbetween different ring systems. In six-membered aromatic systems, thespatial arrangements are specified by the common nomenclature “para” for1,4-substitution, “meta” for 1,3-substitution and “ortho” for1,2-substitution as shown below.

Isotopical Labeling in Described Compounds

The present application further includes all pharmaceutically acceptableisotopically labeled compound [e.g., of formula (I), (Ia), (Ib), (II),(IIa), (III), (IIIa), (IV), (IVa), (V), or (Va)]. An “isotopically” or“radio-labeled” compound is a compound where one or more atoms arereplaced or substituted by an atom having an atomic mass or mass numberdifferent from the atomic mass or mass number typically found in nature(i.e., naturally occurring). For example, in certain embodiments, incompounds [e.g., of formula (I), (Ia), (Ib), (II), (IIa), (III), (IIIa),(IV), (IVa), (V), or (Va)], hydrogen atoms are replaced or substitutedby one or more deuterium or tritium (e.g., hydrogen atoms on a C₁₋₆alkyl or a C₁₋₆ alkoxy are replaced with deuterium, such as d₃-methoxyor 1,1,2,2-d₄-3-methylbutyl).

Certain isotopically labeled compounds [e.g., compounds of formula (I),(Ia), (Ib), (II), (IIa), (III), (IIIa), (IV), (IVa), (V), or (Va)], forexample, those incorporating a radioactive isotope, are useful in drugand/or substrate tissue distribution studies. The radioactive isotopestritium, i.e., ³H, and carbon 14, i.e., ¹⁴C, are particularly useful forthis purpose in view of their ease of incorporation and ready means ofdetection.

Such isotopically labeled compounds are useful in metabolic studies(preferably with ¹⁴C), reaction kinetic studies (with, for example ²H or³H), detection or imaging techniques [such as positron emissiontomography (PET) or single-photon emission computed tomography (SPECT)]including drug or substrate tissue distribution assays, or inradioactive treatment of patients. Further, substitution with heavierisotopes such as deuterium (i.e., ²H) may afford certain therapeuticadvantages resulting from greater metabolic stability, for exampleincreased in vivo half-life or reduced dosage requirements.

Substitution with positron emitting isotopes, such as ¹¹C, ¹⁸F, ¹⁵O, and¹³N, can be useful in Positron Emission Topography (PET) studies forexamining substrate receptor occupancy.

Isotopically labeled compounds [e.g., of formula (I), (Ia), or (Ib)] ortheir corresponding prodrugs can generally be prepared by conventionaltechniques known to those skilled in the art or by processes analogousto those described in the accompanying examples using an appropriateisotopically labeled reagent in place of the non-labeled reagentpreviously employed. Suitable isotopes that may be incorporated incompounds of the present application include but are not limited toisotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine,chlorine, and iodine, such as ²H (also written as D for deuterium), ³H(also written as T for tritium), ¹¹C, ¹³C, ¹⁴C, ¹³N, ¹⁵N, ¹⁵O, ¹⁷O, ¹⁸O,¹⁸F, ³⁵S, ³⁶Cl, ⁸²Br, ⁷⁵Br, ⁷⁶Br, ⁷⁷Br, ¹²³I, ¹²⁴I, ¹²⁵I, ¹³¹I, ³¹P, and³²P.

Isotopically labeled compounds of this application and prodrugs thereofcan generally be prepared by carrying out the procedures disclosed inthe schemes or in the examples and preparations described below bysubstituting a readily available isotopically labeled reagent for anon-isotopically labeled reagent.

Provisos may apply to any of the disclosed categories or embodimentssuch that specific embodiments or species may be excluded from suchcategories or embodiments.

In various embodiments, the compound or set of compounds, such as areused in the inventive methods, can be any one of any of the combinationsand/or sub-combinations of the above-listed embodiments.

Pharmaceutical Compositions

The compositions and methods of the present application may be utilizedto treat a subject, such as a mammal, e.g., human, or a non-humanmammal, in need thereof. When administered to an animal, such as ahuman, the composition or the compound is preferably administered as apharmaceutical composition comprising, for example, a compound of theapplication and a pharmaceutically acceptable carrier. In certainembodiments, the application relates to a pharmaceutical compositioncomprising as active ingredient a therapeutically effective amount of acompound according to formula (I), (Ia), (Ib), (II), (IIa), (III),(IIIa), (IV), (IVa), (V), or (Va), or a pharmaceutically acceptablesalt, solvate, or prodrug thereof, in association with at least onepharmaceutically acceptable carrier, excipient, or diluent.

The term “pharmaceutically acceptable carrier”, as used herein, refersto a pharmaceutically acceptable material, composition or vehicle, suchas a liquid or solid filler, diluent, excipient, solvent orencapsulating material, which can act, for example, to stabilize,increase solubility or to increase the absorption of a compound such asa compound of the application. Each carrier must be “acceptable” in thesense of being compatible with the other ingredients of the formulationand not injurious to the patient.

Pharmaceutically acceptable carriers are well known in the art. Forexample, some examples of materials which can serve as pharmaceuticallyacceptable carriers include, but are not limited to: (1) sugars, such aslactose, glucose, sucrose or dextrans; (2) starches, such as corn starchand potato starch; (3) cellulose, and its derivatives, such as sodiumcarboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4)powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients,such as cocoa butter and suppository waxes; (9) oils, such as peanutoil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil andsoybean oil; (10) glycols, such as glycerol or propylene glycol; (11)polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol;(12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14)buffering agents, such as magnesium hydroxide and aluminum hydroxide;(15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18)Ringer's solution; (19) ethyl alcohol; (20) phosphate buffer solutions;(21) antioxidants, such as ascorbic acid or glutathione; and (22) othernon-toxic compatible substances employed in pharmaceutical formulations,such as chelating agents, low molecular weight proteins or otherstabilizers or excipients.

The choice of a pharmaceutically acceptable carrier, including aphysiologically acceptable agent, depends, for example, on the route ofadministration of the composition. The pharmaceutical composition can bea self-emulsifying or a self-microemulsifying drug delivery system. Thepharmaceutical composition also can be a liposome or other polymermatrix, which can have incorporated therein. Liposomes, for example,which comprise phospholipids or other lipids, are nontoxic,physiologically acceptable and metabolizable carriers that arerelatively simple to make and administer.

Wetting agents, emulsifiers and lubricants, such as sodium laurylsulfate and magnesium stearate, as well as coloring agents, releaseagents, coating agents, sweetening, flavoring and perfuming agents,preservatives and antioxidants can also be present in the compositions.Such liquid compositions may optionally contain:pharmaceutically-acceptable excipients such as suspending agents (forexample, sorbitol, methyl cellulose, sodium alginate, gelatin,hydroxyethylcellulose, carboxymethylcellulose, aluminum stearate gel andthe like); non-aqueous vehicles, e.g., oil (for example, almond oil orfractionated coconut oil), propylene glycol, ethyl alcohol, or water;preservatives (for example, methyl or propyl p-hydroxybenzoate or sorbicacid); wetting agents such as lecithin; and, if desired, flavoring orcoloring agents.

Examples of pharmaceutically acceptable antioxidants include: (1)water-soluble antioxidants, such as ascorbic acid, cysteinehydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfiteand the like; (2) oil-soluble antioxidants, such as ascorbyl palmitate,butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT),lecithin, propyl gallate, alpha-tocopherol, and the like; and (3)metal-chelating agents, such as citric acid, ethylenediamine tetraaceticacid (EDTA), sorbitol, tartaric acid, phosphoric acid, and the like.

A pharmaceutical composition can be administered to a subject by any ofa number of routes of administration including, but not limited to, forexample, orally [for example, drenches as in aqueous or non-aqueoussolutions or suspensions, tablets, pills, capsules (including sprinklecapsules and gelatin capsules), boluses, powders, granules, pastes forapplication to the tongue]; absorption through the oral mucosa (e.g.,sublingually); anally, rectally or vaginally (for example, as a pessary,cream or foam); parenterally (including intramuscularly, intravenously,subcutaneously or intrathecally as, for example, a sterile solution orsuspension); nasally; intraperitoneally; subcutaneously; transdermally(for example as a patch applied to the skin); and topically (forexample, as a cream, ointment or spray applied to the skin, or as an eyedrop). The composition or compound may also be formulated forinhalation. In certain embodiments, the composition or compound may besimply dissolved or suspended in sterile water. Details of appropriateroutes of administration and compositions suitable for same can be foundin, for example, U.S. Pat. Nos. 6,110,973, 5,763,493, 5,731,000,5,541,231, 5,427,798, 5,358,970 and 4,172,896, as well as in patentscited therein. Sterile compositions are also contemplated by theapplication, including compositions that are in accord with national andlocal regulations governing such compositions. Preferably, thecompositions are formulated for intravenous or oral administration.

For oral administration, the compounds the application may be providedin a solid form, such as a tablet, pills, dragees, powers, granules, orcapsule, or as a solution, emulsion, or suspension. To prepare the oralcompositions, the active ingredient is mixed with one or morepharmaceutically acceptable carriers, such as sodium citrate ordicalcium phosphate, and/or any of the following: (1) fillers orextenders, such as starches, lactose, sucrose, glucose, mannitol, and/orsilicic acid; (2) binders, such as, for example, carboxymethylcellulose,alginates, gelatin, polyvinyl pyrrolidone, sucrose and/or acacia; (3)humectants, such as glycerol; (4) disintegrating agents, such asagar-agar, calcium carbonate, potato or tapioca starch, alginic acid,certain silicates, and sodium carbonate; (5) solution retarding agents,such as paraffin; (6) absorption accelerators, such as quaternaryammonium compounds; (7) wetting agents, such as, for example, cetylalcohol and glycerol monostearate; (8) absorbents, such as kaolin andbentonite clay; (9) lubricants, such a talc, calcium stearate, magnesiumstearate, solid polyethylene glycols, sodium lauryl sulfate, andmixtures thereof, (10) complexing agents, such as, modified andunmodified cyclodextrins; (11) coloring agents; (12) emulsifying andsuspending agents, such as, ethoxylated isostearyl alcohols,polyoxyethylene sorbitol, sorbitan esters, microcrystalline cellulose,aluminum metahydroxide, bentonite, agar, and tragacanth; and (13) othernon-toxic compatible substances employed in pharmaceutical formulations,such as, without limitation, buffering agents, perfuming andpreservative agents, sweetening agents, flavoring agents.

Oral tablets may be made by compression or molding, optionally with oneor more accessory ingredients, such as diluents, disintegrating agents,binding agents, lubricating agents, sweetening agents, flavoring agents,coloring agents and preservative agents. Suitable inert fillers includesodium and calcium carbonate, sodium and calcium phosphate, lactose,starch, sugar, glucose, methyl cellulose, magnesium stearate, mannitol,sorbitol, and the like. Exemplary liquid oral excipients includeethanol, glycerol, water, and the like. Starch, polyvinyl-pyrrolidone(PVP), sodium starch glycolate, microcrystalline cellulose, and alginicacid are exemplary disintegrating agents. Binding agents may includehydroxypropylmethyl cellulose, starch and gelatin. The lubricatingagent, if present, may be magnesium stearate, stearic acid, or talc. Ifdesired, the tablets may be coated with a material such as glycerylmonostearate or glyceryl distearate to delay absorption in thegastrointestinal tract, or may be coated with an enteric coating.

Other solid dosage forms of the pharmaceutical compositions, such asdragees, capsules (including sprinkle capsules and gelatin capsules),pills and granules, may optionally be scored or prepared with coatingsand shells, such as enteric coatings and other coatings well known inthe pharmaceutical-formulating art. For example, to prepare hard gelatincapsules, active ingredient(s) may be mixed with a solid, semi-solid, orliquid diluent. Soft gelatin capsules may be prepared by mixing theactive ingredient with water, oil such as peanut oil or olive oil,liquid paraffin, a mixture of mono and di-glycerides of short chainfatty acids, polyethylene glycol 400, or propylene glycol.

The pharmaceutical compositions may also be formulated so as to provideslow or controlled release of the active ingredient therein using, forexample, hydroxypropylmethyl cellulose in varying proportions to providethe desired release profile, other polymer matrices, liposomes and/ormicrospheres. They may be sterilized by, for example, filtration througha bacteria-retaining filter, or by incorporating sterilizing agents inthe form of sterile solid compositions that can be dissolved in sterilewater, or some other sterile injectable medium immediately before use.These compositions may also optionally contain opacifying agents and maybe of a composition that they release the active ingredient(s) only, orpreferentially, in a certain portion of the gastrointestinal tract,optionally, in a delayed manner. Examples of embedding compositions thatcan be used include polymeric substances and waxes. The activeingredient can also be in micro-encapsulated form, if appropriate, withone or more of the above-described excipients.

Liquid dosage forms useful for oral administration includepharmaceutically acceptable emulsions, lyophiles for reconstitution,microemulsions, solutions, suspensions, syrups and elixirs, or may belyophilized or presented as a dry product for reconstitution with wateror other suitable vehicle before use. In addition to the activeingredient, the liquid dosage forms may contain inert diluents commonlyused in the art, such as, for example, water or other solvents,cyclodextrins and derivatives thereof, solubilizing agents andemulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate,ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol,1,3-butylene glycol, oils (in particular, cottonseed, groundnut, corn,germ, olive, castor and sesame oils), glycerol, tetrahydrofuryl alcohol,polyethylene glycols and fatty acid esters of sorbitan, and mixturesthereof.

In addition, formulations of the pharmaceutical compositions foradministration to the mouth may be presented as a mouthwash, or an oralspray, or an oral ointment.

The phrases “parenteral administration” and “administered parenterally”,as used herein, means modes of administration other than enteral andtopical administration, usually by injection, and includes, withoutlimitation, intravenous, intramuscular, intraarterial, intrathecal,intracapsular, intraorbital, intracardiac, intradermal, intranasal,intraperitoneal, transtracheal, subcutaneous, subcuticular,intraarticular, subcapsular, subarachnoid, intraspinal, and intrasternalinjection and infusion.

For parenteral use, the agents of the application may be provided insterile aqueous solutions or suspensions, buffered to an appropriate pHand isotonicity or in parenterally acceptable oil. Suitable aqueousvehicles include Ringer's solution and isotonic sodium chloride.

Such forms may be presented in unit-dose form such as ampoules ordisposable injection devices, in multi-dose forms such as vials fromwhich the appropriate dose may be withdrawn, or in a solid form orpre-concentrate that can be reconstituted into a sterile injectableformulation, such as solutions or dispersions just prior to use, whichmay contain antioxidants, buffers, bacteriostats, solutes which renderthe formulation isotonic with the blood of the intended recipient orsuspending or thickening agents. Illustrative infusion doses range fromabout 1 to 1000 μg/kg/minute of agent admixed with a pharmaceuticalcarrier over a period ranging from several minutes to several days.

Examples of suitable aqueous and nonaqueous carriers that may beemployed in the pharmaceutical compositions of the application includewater, ethanol, polyols (such as glycerol, propylene glycol,polyethylene glycol, and the like), and suitable mixtures thereof,vegetable oils, such as olive oil, and injectable organic esters, suchas ethyl oleate. Proper fluidity can be maintained, for example, by theuse of coating materials, such as lecithin, by the maintenance of therequired particle size in the case of dispersions, and by the use ofsurfactants.

These compositions may also contain adjuvants such as preservatives,wetting agents, emulsifying agents and dispersing agents. Prevention ofthe action of microorganisms may be ensured by the inclusion of variousantibacterial and antifungal agents, for example, paraben,chlorobutanol, phenol sorbic acid, and the like. It may also bedesirable to include isotonic agents, such as sugars, sodium chloride,and the like into the compositions.

In some cases, in order to prolong the effect of a drug, it is desirableto slow the absorption of the drug from subcutaneous or intramuscularinjection. This may be accomplished by the use of a liquid suspension ofcrystalline or amorphous material having poor water solubility. The rateof absorption of the drug then depends upon its rate of dissolution,which, in turn, may depend upon crystal size and crystalline form.Alternatively, delayed absorption of a parenterally administered drugform is accomplished by dissolving or suspending the drug in an oilvehicle.

Injectable depot forms are made by forming microencapsulated matrices ofthe subject compounds in biodegradable polymers such aspolylactide-polyglycolide. Depending on the ratio of drug to polymer,and the nature of the particular polymer employed, the rate of drugrelease can be controlled. Examples of other biodegradable polymersinclude poly(orthoesters) and poly(anhydrides). Depot injectableformulations are also prepared by entrapping the drug in liposomes ormicroemulsions that are compatible with body tissue.

In a preferred embodiment, when such pharmaceutical compositions are forhuman administration, particularly for invasive routes of administration(i.e., routes, such as injection or implantation, that circumventtransport or diffusion through an epithelial barrier), the aqueoussolution is pyrogen-free, or substantially pyrogen-free. The excipientscan be chosen, for example, to effect delayed release of an agent or toselectively target one or more cells, tissues or organs.

For rectal, vaginal, or urethral administration, formulations of thepharmaceutical compositions may be presented as a suppository, which maybe prepared by mixing one or more active compounds with one or moresuitable nonirritating excipients or carriers comprising, for example,cocoa butter, polyethylene glycol, a suppository wax or a salicylate,and which is solid at room temperature, but liquid at body temperatureand, therefore, will melt in the rectum or vaginal cavity and releasethe active compound. Formulations which are suitable for vaginaladministration also include pessaries, tampons, creams, gels, pastes,foams or spray formulations containing such carriers as are known in theart to be appropriate.

For topical applications or transdermal administration, the activecompounds of the present application may be mixed under sterileconditions with a pharmaceutically acceptable carrier, and with anypreservatives, buffers, excipients, or propellants, such as animal andvegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulosederivatives, polyethylene glycols, silicones, bentonites, silicic acid,talc and zinc oxide, or mixtures thereof. Dosage forms for the topicalinclude powders, sprays, ointments, pastes, creams, lotions, gels,solutions, patches and inhalants.

The active compounds may be mixed with a pharmaceutical carrier at aconcentration of about 0.1% to about 10% of drug to vehicle.

Powders and sprays can contain, in addition to an active compound,excipients such as lactose, talc, silicic acid, aluminum hydroxide,calcium silicates and polyamide powder, or mixtures of these substances.Sprays can additionally contain customary propellants, such aschlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, suchas butane and propane.

Transdermal patches have the added advantage of providing controlleddelivery of a compound of the present application to the body. Suchdosage forms can be made by dissolving or dispersing the active compoundin the proper medium. Absorption enhancers can also be used to increasethe flux of the compound across the skin. The rate of such flux can becontrolled by either providing a rate controlling membrane or dispersingthe compound in a polymer matrix or gel.

Ophthalmic formulations, eye ointments, powders, solutions and the like,are also contemplated as being within the scope of this application.Exemplary ophthalmic formulations are described in U.S. Publication Nos.2005/0080056, 2005/0059744, 2005/0031697 and 2005/004074 and U.S. Pat.No. 6,583,124, the contents of which are incorporated herein byreference. If desired, liquid ophthalmic formulations have propertiessimilar to that of lacrimal fluids, aqueous humor or vitreous humor orare compatible with such fluids. A preferred route of administration islocal administration (e.g., topical administration, such as eye drops,or administration via an implant).

Alternatively or additionally, compositions can be formulated fordelivery via a catheter, stent, wire, or other intraluminal device.Delivery via such devices may be especially useful for delivery to thebladder, urethra, ureter, rectum, or intestine.

Methods of introduction may also be provided by rechargeable orbiodegradable devices. Various slow release polymeric devices have beendeveloped and tested in vivo in recent years for the controlled deliveryof drugs, including proteinacious biopharmaceuticals. A variety ofbiocompatible polymers (including hydrogels), including bothbiodegradable and non-degradable polymers, can be used to form animplant for the sustained release of a compound at a particular targetsite.

A physician or veterinarian having ordinary skill in the art can readilydetermine and prescribe the therapeutically effective amount of thepharmaceutical composition required. The term “therapeutically effectiveamount” or “dose”, or “dosage”, as used herein, refers to an amount ordose sufficient to generally bring about the desired therapeutic benefitor an amount sufficient to modulate the biological activity of thetarget receptor in subjects needing such treatment.

Effective amounts or dosages of the compounds of the application may beascertained by routine methods, such as modeling, dose escalation, orclinical trials, taking into account routine factors. Actual dosagelevels of the active ingredients in the pharmaceutical compositions maybe varied. In general, a suitable daily dose of an active compound usedin the compositions and methods of the application will be that amountof the compound that is the lowest dose effective to produce atherapeutic effect.

The selected dosage level will depend upon a variety of factorsincluding the activity of the particular compound or combination ofcompounds employed, or the salts, solvate, and prodrug thereof, theroute of administration, the time of administration, the rate ofexcretion of the particular compound(s) being employed, the duration ofthe treatment, other drugs, compounds and/or materials used incombination with particular compound(s) employed, age, sex, weight,condition, general health, prior medical history of the patient beingtreated, and the preference and experience of the physician orveterinarian in charge, and like factors well known in the medical arts.

For example, in choosing a regimen for a subject, such as a patient, itcan frequently be necessary to begin with a higher dosage and when thecondition is under control to reduce the dosage. In another example, itis also possible to start at a dosage of the pharmaceutical compositionfor compound at levels lower than that required in order to achieve thedesired therapeutic effect and gradually increase the dosage until thedesired effect is achieved.

The compounds of the application are effective over a wide dosage range.For example, in the treatment of adult humans, dosages from about 0.05to about 5000 mg, preferably from about 1 to about 2000 mg, and morepreferably between about 2 and about 2000 mg per day can be used. Atypical dosage is about 10 mg to about 1000 mg per day, or 25 to 200 mgper day, or 50 to 100 mg per day, or less than 100 mg per day.

In some embodiments, the compounds of the application are dispensed inunit dosage form including from about 0.05 mg to about 1000 mg of activeingredient together with a pharmaceutically acceptable carrier per unitdosage. In other embodiments, a unit dosage form includes from about 10to about 200 mg of active ingredient. In other embodiments, dosage formssuitable for oral, nasal, pulmonal or transdermal administration includefrom about 125 μg to about 1250 mg, preferably from about 250 μg toabout 500 mg, and more preferably from about 2.5 mg to about 250 mg, ofthe compounds admixed with a pharmaceutically acceptable carrier ordiluent. Methods to determine efficacy and dosage are known to thoseskilled in the art (Isselbacher et al. (1996) Harrison's Principles ofInternal Medicine 13^(ed)., 1814-1882, herein incorporated byreference).

Dosage forms can be administered daily or more than once a day, such astwice or thrice daily. Alternatively dosage forms can be administeredless frequently than daily, such as every other day, or weekly, if foundto be advisable by a prescribing physician. A larger dosage can bedelivered by multiple administrations of the agent. In some embodiments,dosage forms are administered once, twice, or thrice daily. In preferredembodiments, the active compound will be administered once daily. Onceimprovement of the patient's disease has occurred, the dose may beadjusted for maintenance treatment. For example, the dosage or thefrequency of administration, or both, may be reduced as a function ofthe symptoms, to a level at which the desired therapeutic orprophylactic effect is maintained. Of course, if symptoms have beenalleviated to an appropriate level, treatment may cease. Patients may,however, require intermittent treatment on a long-term basis upon anyrecurrence of symptoms. Patients may also require chronic treatment on along-term basis.

Methods and Uses

In various embodiments, compounds of the application can be used tomodulate, such as to activate (agonist), or to block activation of(antagonist), an orexin receptor. Accordingly, in various embodiments,the application provides a method of modulating an orexin receptorcomprising contacting the receptor with an effective amount orconcentration of a compound of the application. The orexin receptor canbe OX₁ or OX₂. In various embodiments, the compound of the applicationis an antagonist of an orexin receptor such as OX₁ or OX₂, or both, andcan be a selective inhibitor of one or the other. In variousembodiments, contacting can take place in vivo within tissues of apatient, such as a human patient. In various embodiments, modulation ofan orexin receptor, for example, antagonism of orexin-1, by a compoundof the application can be used to treat a disease, disorder, or medicalcondition in a patient, as described herein.

In various embodiments, the application provides a method of treating adisease, disorder, or medical condition in a patient, such as treating adisease, disorder, or medical condition in which modulation of an orexinreceptor is medically indicating, comprising administering to thesubject, such as a patient, a compound of the application in a dose, ata frequency, and for duration to provide a beneficial effect to thesubject. Modulation, such as agonism or antagonism, of an orexinreceptor can be medically indicated in treatment of a disease, disorder,or medical condition wherein the orexin receptor plays a metabolic orregulatory role. Certain such conditions can be treated by selectivemodulation of a single class of orexin receptor, such as modulation ofOX₁ while OX₂ is not influenced by administration of the compound of theapplication at the dose provided. In various embodiments, compounds ofthe application can be orexin-1 antagonists, and some of those areselective orexin-1 antagonists with respect to orexin-2. By “selective”is meant that one receptor is modulated at concentrations of thecompound at least 10 times lower than the concentrations at which thecomparative receptor is modulated by that compound. Accordingly, invarious embodiments, the compound of the application can be a selectivemodulator, e.g., an antagonist, of orexin receptor OX₁. In otherembodiments, the compound of the application can be a selectivemodulator (e.g., antagonist) of an orexin receptor OX₂. In furtherembodiments, the compound of the application can further modulate othertypes or classes of receptors having affinity for one of more forms ofthe orexin class of natural peptidic ligands.

In various embodiments, the application provides a use of a compound ofthe application for treatment of a disease, disorder, or medicalcondition in a patient. For example, a compound of the application canbe used in the preparation of a medicament for administration to apatient suffering from a disease, disorder, or medical condition. Morespecifically, the disease, disorder, or medical condition can comprisean eating disorder, obesity, alcoholism or an alcohol-related disorder,drug abuse or addiction, a sleep disorder, a cognitive dysfunction in apsychiatric or neurologic disorder, depression, anxiety, panic disorder,schizophrenia, Alzheimer's disease, aggression associated withneurological disorders such as Alzheimer's disease, and aggressionassociated with neurodevelopmental disorders such as autism, Parkinson'sdisease, Huntington's chorea, head ache, migraine, pain,gastrointestinal diseases, epilepsy, inflammations, immune-relateddiseases, endocrine-related diseases, cancer, hypertension, behaviordisorder, mood disorder, manic depression, dementia, sex disorder,psychosexual disorder, and renal disease. Drug or substance abuse oraddiction includes relapse. These may include abuse of or addiction tococaine, opiates, amphetamines, nicotine, alcohol, cannabis, heroin,and/or any other drug of abuse.

In other embodiments, the disease, disorder, or medical condition isnarcolepsy, insomnia, learning disorders, memory disorders, depression,anxiety, addiction, obsessive compulsive disorder, affective neurosis,depressive neurosis, anxiety neurosis, dysthymic disorder, behaviordisorder, mood disorder, sexual dysfunction, psychosexual dysfunction,sex disorder, schizophrenia, manic depression, delirium, dementia,severe mental retardation or dyskinesias (such as Huntington's Diseaseor Tourette Syndrome), eating disorders (such as anorexia, bulimia,cachexia, or obesity), addictive feeding behaviors, binge/purge feedingbehaviors, cardiovascular diseases, diabetes, appetite/taste disorders,emesis, vomiting, nausea, asthma, cancer, Parkinson's Disease, Cushing'sSyndrome/Disease, basophile adenoma, prolactinoma, hyperprolactinemia,hypophysis tumor/adenoma, hypothalamic diseases, inflammatory boweldisease, gastric dyskinesia, gastric ulcers, Froehlich's Syndrome,adrenohypophysis disease, hypophysis diseases, adrenohypophysishypofunction, adrenohypophysis hyperfunction, hypothalamic hypogonadism,Kallman's syndrome (anosmia, hyposmia), functional or psychogenicamenorrhea, hypopituitarism, hypothalamic hypothyroidism,hypothalamic-adrenal dysfunction, idiopathic hyperprolactinemia,hypothalamic disorders of growth hormone deficiency, idiopathic growthdeficiency, dwarfism, gigantism, acromegaly, disturbed biological andcircadian rhythms, sleep disturbances associated with disease such asneurological disorders, neuropathic pain, diabetic neuropathy, andrestless leg syndrome, heart and lung diseases, acute and congestiveheart failure, hypotension, hypertension, urinary retention,osteoporosis, angina pectoris, myocardial infarction, ischemic orhemorrhagic stroke, subsrachnoic hemorrhage, ulcers, allergies, benignprostatic hypertrophy, chronic renal failure, renal disease, impairedglucose tolerance, migraine, episodic migraine, headache disorders (suchas tension-type headache, cluster headache, other trigeminal autonomiccephalalgias, other primary headaches such as hemicranias continua,secondary headaches, cranial neuralgia, or central or primary facialpain), hyperalgesia, pain, enhanced or exaggerated sensitivity to painsuch as hyperalgesia, causalgia, or allodynia, acute pain, burn pain,atypical facial pain, neuropathic pain, back pain, complex regional painsyndrome I or II, arthritic pain, sports injury pain, pain related toinfection (e.g., HIV), post-chemotherapy pain, post-stroke pain,post-operative pain, neuralgia, emesis, nausea, vomiting, conditionsassociated with visceral pain (such as irritable bowel syndrome orangina), urinary bladder incontinence (e.g., urge incontinence),tolerance to narcotics or withdrawal from narcotics, sleep disorders,sleep apnea, parasomnia, jet lag syndrome, neurodegenerative disorders,disinhibition-dementia-parkinsonism-amyotrophy complex,pallido-ponto-nigral degeneration, epilepsy, seizure disorders, or otherdiseases related to general orexin system dysfunction.

In still other embodiments, the compounds described herein are useful ina method of treating disorders including, but not limited to, sleepdisorders, sleep disturbances, including enhancing sleep quality,improving sleep quality, increasing sleep efficiency, augmenting sleepmaintenance; increasing the ratio of the time that a subject sleepsrelative to the time that a subject is attempting to sleep; improvingsleep initiation; decreasing sleep latency or onset (the time it takesto fall asleep); decreasing difficulties in falling asleep; increasingsleep continuity; decreasing the number of awakenings during sleep;decreasing intermittent wakings during sleep; decreasing nocturnalarousals; decreasing the time spent awake following the initial onset ofsleep; increasing the total amount of sleep; reducing the fragmentationof sleep; altering the timing, frequency, or duration of REM sleepbouts; altering the timing, frequency, or duration of slow wave (such asstages 3 or 4) sleep bouts; increasing the amount and percentage ofstage 2 sleep; promoting slow wave sleep; enhancing EEG-delta activityduring sleep; decreasing nocturnal arousals, especially early morningawakenings; increasing daytime alertness; reducing daytime drowsiness;treating or reducing excessive daytime sleepiness; increasingsatisfaction with the intensity of sleep; increasing sleep maintenance;idiopathic insomnia; sleep problems; insomnia, hypersomnia, idiopathichypersomnia, repeatability hypersomnia, intrinsic hypersomnia,narcolepsy, interrupted sleep, sleep apnea, wakefulness, nocturnalmyoclonus, REM sleep interruptions, jet-lag, shift workers' sleepdisturbances, dyssomnias, night terror, insomnias associated withdepression, emotional/mood disorders, Alzheimer's disease, or cognitiveimpairment, as well as sleep walking and enuresis, and sleep disordersthat accompany aging; Alzheimer's sundowning; conditions associated withcircadian rhythmicity as well as mental and physical disordersassociated with travel across time zones and with rotating shift-workschedules, conditions due to drugs that cause reductions in REM sleep asa side effect; fibromyalgia; syndromes that are manifested bynon-restorative sleep and muscle pain; sleep apnea that is associatedwith respiratory disturbances during sleep; conditions that result froma diminished quality of sleep; increasing learning; augmenting memory;increasing retention of memory; eating disorders associated withexcessive food intake and complications associated therewith, compulsiveeating disorders, obesity (due to any cause, whether genetic orenvironmental), obesity-related disorders including overeating andbulimia nervosa, hypertension, diabetes, elevated plasma insulinconcentrations and insulin resistance, dyslipidemias, hyperlipidemia,endometrial, breast, prostate and colon cancer, osteoarthritis,obstructive sleep apnea, cholelithiasis, gallstones, heart disease,abnormal heart rhythms and arrythmias, myocardial infarction, congestiveheart failure, coronary heart disease, sudden death, stroke, polycysticovary disease, craniopharyngioma, the Prader-Willi Syndrome, Frohlich'ssyndrome, GH-deficient subjects, normal variant short stature, Turner'ssyndrome, and other pathological conditions showing reduced metabolicactivity or a decrease in resting energy expenditure as a percentage oftotal fat-free mass, e.g., children with acute lymphoblastic leukemia,metabolic syndrome, also known as syndrome X, insulin resistancesyndrome, reproductive hormone abnormalities, sexual and reproductivedysfunction, such as impaired fertility, infertility, hypogonadism inmales and hirsutism in females, fetal defects associated with maternalobesity, gastrointestinal motility disorders, such as obesity-relatedgastro-esophageal reflux, respiratory disorders, such asobesity-hypoventilation syndrome (Pickwickian syndrome), breathlessness,cardiovascular disorders, inflammation, such as systemic inflammation ofthe vasculature, arteriosclerosis, hypercholesterolemia, hyperuricaemia,lower back pain, gallbladder disease, gout, kidney cancer, increasedanesthetic risk, reducing the risk of secondary outcomes of obesity,such as reducing the risk of left ventricular hypertrophy; diseases ordisorders where abnormal oscillatory activity occurs in the brain,including depression, migraine, neuropathic pain, Parkinson's disease,psychosis, or schizophrenia, as well as diseases or disorders wherethere is abnormal coupling of activity, particularly through thethalamus; enhancing cognitive function; enhancing memory; increasingmemory retention; increasing immune response; increasing immunefunction; hot flashes; night sweats; extending life span; schizophrenia;muscle-related disorders that are controlled by theexcitation/relaxation rhythms imposed by the neural system such ascardiac rhythm and other disorders of the cardiovascular system;conditions related to proliferation of cells such as vasodilation orvasorestriction and blood pressure; cancer; cardiac arrhythmia;hypertension; congestive heart failure; conditions of thegenital/urinary system; disorders of sexual function and fertility;adequacy of renal function; responsivity to anesthetics; mood disorders,such as depression or more particularly depressive disorders, forexample, single episodic or recurrent major depressive disorders anddysthymic disorders, or bipolar disorders, for example, bipolar Idisorder, bipolar II disorder, and cyclothymic disorder, mood disordersdue to a general medical condition, and substance-induced mooddisorders; anxiety disorders including acute stress disorder,agoraphobia, generalized anxiety disorder, obsessive-compulsivedisorder, panic attack, panic disorder, post-traumatic stress disorder,separation anxiety disorder, social phobia, specific phobia,substance-induced mood disorders; anxiety disorders including acutestress disorder, agoraphobia, generalized anxiety disorder,obsessive-compulsive disorder, panic attack, panic disorder,post-traumatic stress disorder, separation anxiety disorder, socialphobia, specific phobia, substance-induced anxiety disorder and anxietydue to a general medical condition; acute neurological and psychiatricdisorders such as cerebral deficits subsequent to cardiac bypass surgeryand grafting, stroke, ischemic stroke, cerebral ischemia, spinal cordtrauma, head trauma, perinatal hypoxia, cardiac arrest, hypoglycemicneuronal damage; Huntington's Chorea; amyotrophic lateral sclerosis;multiple sclerosis; ocular damage; retinopathy; cognitive disorders;idiopathic and drug-induced Parkinson's disease; muscular spasms anddisorders associated with muscular spasticity including tremors,epilepsy, convulsions; cognitive disorders including dementia(associated with Alzheimer's disease, ischemia, trauma, vascularproblems or stroke, HIV disease, Parkinson's disease, Huntington'sdisease, Pick's disease, Creutzfeldt-Jacob disease, perinatal hypoxia,other general medical conditions or substance abuse); delirium, amnesticdisorders or age related cognitive decline; schizophrenia or psychosisincluding schizophrenia (paranoid, disorganized, catatonic orundifferentiated), schizophreniform disorder, schizoaffective disorder,delusional disorder, brief psychotic disorder, shared psychoticdisorder, psychotic disorder due to a general medical condition andsubstance-induced psychotic disorder; substance-related disorders andaddictive behaviors (including substance-induced delirium, persistingdementia, persisting amnestic disorder, psychotic disorder or anxietydisorder; tolerance, addictive feeding, dependence or withdrawal fromsubstances including alcohol, amphetamines, cannabis, cocaine,hallucinogens, inhalants, nicotine, opioids, phencyclidine, sedatives,hypnotics, or anxiolytics); movement disorders, including akinesias andakinetic-rigid syndromes (including Parkinson's disease, drug-inducedparkinsonism, postencephalitic parkinsonism, progressive supranuclearpalsy, multiple system atrophy, corticobasal degeneration,parkinsonism-ALS dementia complex and basal ganglia calcification),chronic fatigue syndrome, fatigue, including Parkinson's fatigue,multiple sclerosis fatigue, fatigue caused by a sleep disorder or acircadian rhythm disorder, medication-induced parkinsonism (such asneuroleptic-induced parkinsonism, neuroleptic malignant syndrome,neuroleptic-induced acute dystonia, neuroleptic-induced acute akathisia,neuroleptic-induced tardive dyskinesia and medication-induced posturaltremor), Gilles de la Tourette's syndrome, epilepsy, and dyskinesiasincluding tremor (such as rest tremor, essential tremor, postural tremorand intention tremor), chorea (such as Sydenham's chorea, Huntington'sdisease, benign hereditary chorea, neuroacanthocytosis, symptomaticchorea, drug-induced chorea and hemiballism), myoclonus (includinggeneralised myoclonus and focal myoclonus), tics (including simple tics,complex tics and symptomatic tics), restless leg syndrome and dystonia(including generalized dystonia such as iodiopathic dystonia,drug-induced dystonia, symptomatic dystonia and paroxymal dystonia, andfocal dystonia such as blepharospasm, oromandibular dystonia, spasmodicdysphonia, spasmodic torticollis, axial dystonia, dystonic writer'scramp and hemiplegic dystonia); attention deficit/hyperactivity disorder(ADHD); conduct disorder; migraine (including migraine headache);urinary incontinence; substance tolerance, substance withdrawal(including, substances such as opiates, nicotine, tobacco products,alcohol, benzodiazepines, cocaine, sedatives, hypnotics, etc.);psychosis; schizophrenia; anxiety (including generalized anxietydisorder, panic disorder, and obsessive compulsive disorder); mooddisorders (including depression, mania, bipolar disorders); trigeminalneuralgia; hearing loss; tinnitus; neuronal damage including oculardamage; retinopathy; macular degeneration of the eye; emesis; brainedema; pain, including acute and chronic pain states, severe pain,intractable pain, inflammatory pain, neuropathic pain, post-traumaticpain, bone and joint pain (osteoarthritis), repetitive motion pain,dental pain, cancer pain, myofascial pain (muscular injury,fibromyalgia), perioperative pain (general surgery, gynecological),chronic pain, neuropathic pain, post-traumatic pain, trigeminalneuralgia, migraine and migraine headache.

In other embodiments, the disease, disorder, or medical condition is aneating disorder, obesity, alcoholism or an alcohol-related disorder,drug abuse or addiction, a sleep disorder, a cognitive dysfunction in apsychiatric or neurologic disorder, depression, anxiety, panic disorder,schizophrenia, Alzheimer's disease, Parkinson's disease, Huntington'schorea, head ache, migraine, pain, gastrointestinal diseases, epilepsy,inflammations, immune-related diseases, ulcers, irritable bowelsyndrome, diarrhea, gastroesophageal reflux, endocrine-related diseases,cancer, hypertension, behavior disorder, mood disorder, manicdepression, dementia, sex disorder, psychosexual disorder, and renaldisease.

In still other embodiments, the disease, disorder, or medical conditionis substance addiction (including relapse), panic disorder, anxiety,post-traumatic stress disorder, pain, depression, seasonal affectivedisorder, an eating disorder, or hypertension.

Thus, in specific embodiments the present application provides methodsfor: enhancing the quality of sleep; augmenting sleep maintenance;increasing REM sleep; increasing stage 2 sleep; decreasing fragmentationof sleep patterns; treating insomnia; enhancing cognition; increasingmemory retention; treating or controlling obesity; treating orcontrolling depression; treating, controlling, ameliorating or reducingthe risk of epilepsy, including absence epilepsy; treating orcontrolling pain, including neuropathic pain; treating or controllingParkinson's disease; treating or controlling psychosis; or treating,controlling, ameliorating or reducing the risk of schizophrenia, in asubject in need thereof which comprises administering to the patient atherapeutically effective amount of a compound of the presentapplication.

It is believed that antagonism of orexin-1 is medically indicated forthe treatment of the above-listed conditions. By antagonism is meantblocking a receptor, in this case an orexin receptor, without causing itto transduce a signal. That is, antagonism results in blocking anendogenous or exogenous ligand from activating, or causing antagonism,of the receptor.

It is within ordinary skill to evaluate any compound disclosed andclaimed herein for effectiveness in modulation of an orexin receptor andin the various cellular assays using the procedures described above orfound in the scientific literature. Accordingly, the person of ordinaryskill can prepare and evaluate any of the claimed compounds withoutundue experimentation. Any compound found to be an effective modulator,agonist or antagonist, can likewise be tested in animal models and inhuman clinical studies using the skill and experience of theinvestigator to guide the selection of dosages and treatment regimens.

In certain embodiments, the application comprises a method forconducting a pharmaceutical business, by determining an appropriateformulation and dosage of a compound of the application for treating orpreventing any of the diseases or conditions as described herein,conducting therapeutic profiling of identified formulations for efficacyand toxicity in animals, and providing a distribution network forselling an identified preparation as having an acceptable therapeuticprofile. In certain embodiments, the method further includes providing asales group for marketing the preparation to healthcare providers.

In certain embodiments, the application relates to a method forconducting a pharmaceutical business by determining an appropriateformulation and dosage of a compound of the application for treating orpreventing any of the disease or conditions as described herein, andlicensing, to a third party, the rights for further development and saleof the formulation.

The term “healthcare providers” refers to individuals or organizationsthat provide healthcare services to a person, community, etc. Examplesof “healthcare providers” include doctors, hospitals, continuing careretirement communities, skilled nursing facilities, subacute carefacilities, clinics, multispecialty clinics, freestanding ambulatorycenters, home health agencies, and HMO's.

Drug Combinations

The compounds of the present application may be used in pharmaceuticalcompositions or methods in combination with one or more additionalactive ingredients in the treatment of the diseases and disordersdescribed herein. Further additional active ingredients include othertherapeutics or agents that mitigate adverse effects of therapies forthe intended disease targets. Such combinations may serve to increaseefficacy, ameliorate other disease symptoms, decrease one or more sideeffects, or decrease the required dose of an inventive compound. Incertain embodiments, such combination provides an additive effect,wherein an additive effect refers to the sum of each of the effects ofindividual administration of the compound of the application and one ormore additional therapeutic agent(s). In other embodiments, suchcombination provides a synergistic effect, in which the therapeuticeffect exceeds the sum of each of the effects of individualadministration of the compound of the application and one or moreadditional therapeutic agent(s).

The additional active ingredients may be administered in a separatepharmaceutical composition from a compound of the present application ormay be included with a compound of the present application in a singlepharmaceutical composition. The additional active ingredients may beadministered simultaneously with, prior to, or after administration of acompound of the present application. Actual dosage levels of the activeingredients in the pharmaceutical compositions may be varied so as toobtain an amount of the active ingredient that is effective to achievethe desired therapeutic response for a particular subject, such as apatient, composition, and mode of administration, without being toxic tothe subject.

Combination agents include additional active ingredients are those thatare known or discovered to be effective in treating the diseases anddisorders described herein, including those active against anothertarget associated with the disease. For example, compositions andformulations of the application, as well as methods of treatment, canfurther comprise other drugs or pharmaceuticals, e.g., other activeagents useful for treating or palliative for the target diseases orrelated symptoms or conditions. For example, additional activeingredients include those that are known to be useful for enhancingsleep quality and preventing and treating sleep disorders and sleepdisturbances, anti-diabetic agents, cardiovascular therapies,anti-obesity agents, other orexin receptor antagonists, painmedications, anti-depressants, anti-anxiety agents, cognition-enhancingagents, anti-Alzheimer's Disease therapies, and other activeingredients. Exemplary active pharmaceutical ingredients and othertherapies that are suitable for combination with the presently describedcompounds include those listed in PCT Publ. No. WO2008/147518 at pages23-29, which is hereby incorporated by reference. The pharmaceuticalcompositions of the any compound described herein may additionalcomprise one or more of such active agents, and methods of treatment mayadditionally comprise administering an effective amount of one or moreof such active agents.

EXAMPLES

The following examples are offered to illustrate but not to limit theapplication. One of skill in the art will recognize that the followingsynthetic reactions and schemes may be modified by choice of suitablestarting materials and reagents in order to access other compounds ofFormula (I), (Ia), (Ib), (II), (IIa), (III), (IIIa), (IV), (IVa), (V),or (Va), or a pharmaceutically acceptable salt thereof.

Example 1: Synthetic Protocols

Exemplary chemical entities useful in methods of the application willnow be described by reference to illustrative synthetic schemes fortheir general preparation below and the specific examples that follow.Artisans will recognize that, to obtain the various compounds herein,starting materials may be suitably selected so that the ultimatelydesired substituents will be carried through the reaction scheme with orwithout protection as appropriate to yield the desired product.Alternatively, it may be necessary or desirable to employ, in the placeof the ultimately desired substituent, a suitable group that may becarried through the reaction scheme and replaced as appropriate with thedesired substituent. Furthermore, one of skill in the art will recognizethat the transformations shown in the schemes below may be performed inany order that is compatible with the functionality of the particularpendant groups. Each of the reactions depicted in the general schemes ispreferably run at a temperature from about 0° C. to the refluxtemperature of the organic solvent used. Unless otherwise specified, thevariables are as defined above in reference to Formula (I), (Ia), (Ib),(II), (IIa), (III), (IIIa), (IV), (IVa), (V), or (Va). Isotopicallylabeled compounds as described herein are prepared according to themethods described below, using suitably labeled starting materials. Suchmaterials are generally available from commercial suppliers ofradiolabeled chemical reagents.

Terms and Abbreviations

-   ACN acetonitrile;-   aq aqueous;-   Atm atmospheric pressure;-   Boc t-butoxycarbonyl;-   Borax di-sodium tetraborate or sodium borate or sodium tetraborate;-   Cbz benzyloxycarbonyl;-   CDI 1,1′-carbonyldiimidazole;-   DAST Diethylaminosulfur trifluoride-   dba dibenzylideneacetone;-   DCM dichloromethane;-   DEA diethylamine;-   DIBAL-H diisobutylaluminium hydride;-   DIPEA diisopropylethylamine;-   DME 1,2-dimethoxyethane;-   DMF N,N-dimethyl formamide;-   DMSO dimethyl sulfoxide;-   Et₂O diethyl ether;-   EtOAc ethyl acetate;-   EtOH ethanol;-   eq. or equiv. equivalent;-   h hour(s);-   HATU 2-(7-aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium    hexafluorophosphate;-   HBTU O-benzotriazole-N,N,N′,N′-tetramethyluronium    hexafluorophosphate-   HPLC high performance liquid chromatography;-   LCMS liquid chromatography mass spectrometry;-   LDA lithium diisopropylamide;-   LiHMDS lithium bis(trimethylsilyl)amide;-   MeOH methanol;-   min minute(s);-   MS mass spectrometry;-   MW microwave(s);-   NH₄OAc ammonium acetate;-   NMR nuclear magnetic resonance;-   ox oxidation;-   Psi pounds per square inch;-   quant. quantitative;-   RCM ring closing metathesis;-   r.t. room temperature;-   sat. saturated;-   SFC supercritical fluid chromatography;-   T3P propylphosphonic anhydride;-   TFA trifluoroacetic acid;-   THE tetrahydrofuran;-   TLC thin layer chromatography;-   TMEDA tetramethylethylenediamine;-   UPLC ultra performance liquid chromatography.

General Synthetic Scheme

In some embodiments, compounds of formula (I), (Ia), (Ib), (II), (IIa),(III), (IIIa), (IV), (IVa), (V), or (Va) of the application, whereinboth X and X′ are F and Z is NR², can be prepared according to thegeneral synthetic scheme shown in Scheme 1.

In some embodiments, compounds of formula (I), (Ia), (II), (IIa), (III),(IIIa), (IV), (IVa), (V), or (Va) of the application, wherein X is F, X′is H and Z is NR², can be prepared according to the general syntheticscheme shown in Scheme 2.

In some embodiments, compounds of formula (I), (Ia), (Ib), (II), (IIa),(III), (IIIa), (IV), (IVa), (V), or (Va) of the application, wherein Xis F, X′ is H or halogen, such as F, and Z is 0, can be preparedaccording to the general synthetic scheme shown in Scheme 3.

Synthesis of Compounds (b)-(u) 3-Methylpiperidine-2-carboxylic acidhydrochloride (b)

PtO₂ (10 g, 44.0 mol) was added to the mixture of 3-Methylpicolinic acid(100 g, 730 mmol) in 2 L of EtOH/H₂O (1/1) with 200 mL of conc. HCl (36%wt). The reaction was stirred at RT under a hydrogen atmosphere at 3 MPafor 25 h, ¹H-NMR indicated completion of reaction. The reaction wasfiltered through diatomaceous earth (ca. 1 cm) and concentrated to yieldthe title compound as a white solid (131 g, 730 mmol, 100%), which wasused for next step without further purification. ¹H NMR (MeOD, 400 MHz)δ 4.13-4.11 (m, 1H), 3.40-3.33 (m, 1H), 3.05-2.99 (m, 1H), 2.61-2.58 (m,1H), 1.92-1.72 (m, 4H), 1.09 (d, J=7.0 Hz, 3H).

1-(Benzyloxycarbonyl)-3-methylpiperidine-2-carboxylic acid (c)

Compound b (79 g, 0.44 mol) was dissolved in 2 M NaOH/THF (1/1 v/v, 1500mL) and cooled to 0° C. Benzyl chloroformate (113 g, 0.67 mol) was thenadded dropwise and the reaction was stirred at RT for 48 h. The reactionwas concentrated to remove the THF, and then extracted with toluene(3×100 mL) to remove excess CbzCl and benzyl alcohol. The organic layerwas discarded. The aqueous layer was acidified (pH˜2) with conc. HCl andthe product was extracted with EtOAc (150 mL×4), dried over MgSO₄,filtered, and concentrated in vacuo. The resulting colorless oil slowlysolidified (103 g, 84%) and was used in the next step without furtherpurification. ¹H NMR (CDCl₃, 400 MHz) δ 7.40-7.37 (m, 5H), 5.19 (m, 2H),4.95-4.72 (m, 1H), 4.14-4.03 (m, 1H), 3.36-3.25 (m, 1H), 1.93-1.53 (m,5H), 1.20-1.05 (m, 3H). ESI-MS (m/z): 263.93 [M+1]⁺.

(2S,3R)-1-(Benzyloxycarbonyl)-3-methylpiperidine-2-carboxylic acid (d)

Compound c (55 g, 0.20 mmol) was dissolved in i-PrOH (400 mL).D-Tyrosine Hydrazide (23 g, 0.12 mol) was added to give a heterogenousmixture which was heated to reflux. MeOH was added in 100 mL portionsuntil a homogenous solution was formed. The reaction was stirred for 1 hat this temperature evaporating off some of the MeOH in the process.When the reaction just becomes cloudy, heating was turned off, and thereaction was allowed to cool to rt with vigorous stirring which yieldeda thick slurry. The reaction mixture was filtered and washed with i-PrOH(100 mL) to yield a colorless solid (˜40 g, ee˜94%). Recrystallizationfrom IPA/MeOH afforded a colorless solid (36 g, >99% ee, 38%).

The colorless solid was dissolved in EtOAc (400 mL) and washed with 1 MHCl (100 mL×3), brine (100 mL) and dried over MgSO₄. Removal of solventunder reduced pressure afforded a colorless oil as compound d (>99.% ee,21 g) which slowly solidified.

(2S,3R)-3-methylpiperidine-2-carboxylic acid (e)

To a solution of compound d (51 g, 0.18 mol) in EtOAc under argon wasadded cat. 10% Pd/C. The reaction was evacuated and purged with hydrogen(2×) from a balloon, and then stirred under a balloon of H₂ untilstarting material was consumed as judged by reverse-phase analyticalHPLC (˜30 h). The reaction mixture was filtered through celite. Thecelite was washed well with hot MeOH. The combined filtrates wereconcentrated in vacuo to yield the title compound e as a near colorlesssolid (25.5 g, 99%) which was used without further purification. ¹H NMR(MeOD, 400 MHz) δ 3.58 (d, 1H), 3.3 (m, 1H), 2.95-2.85 (m, 1H),2.60-2.50 (m, 1H), 1.91-1.62 (m, 4H), 1.16 (d, 3H).

(2S,3R)-methyl 3-methylpiperidine-2-carboxylate, Chloride Salt (f)

Excess HCl in MeOH (from AcCl and MeOH) was added to the crude aminoacid compound e (25.5 g) from the previous step and the solution waswarmed to reflux until starting material was consumed. An aliquot wasremoved after 12 h and concentrated in vacuo-crude ¹H-NMR indicatedcomplete conversion. The reaction was then concentrated in vacuo toafford the title compound as a pale yellow solid (34 g, 100% yield)which was used without further purification. ¹H NMR (MeOD, 400 MHz) δ4.22 (m, 1H), 3.9 (s, 3H), 3.42-3.38 (m, 1H), 3.10-3.0 (m, 1H),2.63-2.55 (m, 1H), 1.97-1.70 (m, 4H), 1.03 (d, 3H).

(2S,3R)-1-tert-Butyl 2-methyl 3-methylpiperidine-1,2-dicarboxylate (g)

To a solution of the crude salt compound f (34 g, 0.176 mol) from theprevious step in THE (350 mL)/H₂O (250 mL) at 0° C. was added DIEA (92mL, 3 eq) followed by BOC₂O (76 g, 2 eq). The reaction was allowed towarm to rt O/N and stirred for ˜24 h. The reaction was then concentratedto remove the THF, and then diluted with EtOAc, and washed with 1M HCl(3×), NaHCO₃ (1×), brine, dried (MgSO₄) and concentrated. The resultingcrude colorless oil was contaminated with BOC₂O, but was used withoutfurther purification. 1H NMR (CDCl3, 400 MHz) δ 4.65 (br s, 1.0H),4.0-3.9 (m, 1.0H), 3.69 (s, 3.0H), 3.3-3.15 (m, 1.0H), 1.9-1.8 (m,1.0H), 1.8-1.65 (m, 1.0H), 1.65-1.5 (m, 3.0H), 1.44 (s, 9.0H), 1.01 (d,3.0H) ppm; ESI-MS (m/z): 280.89 [M+Na]+.

(2S,3R)-1-tert-Butyl 2-methyl 3-methyl-6-oxopiperidine-1,2-dicarboxylate(h)

To a 0° C. solution of the crude carbamate compound g from the previousstep and RuCl₃ (400 mg, 1 mol %) in CH₃CN (150 mL) was added dropwise asolution of NaBrO₃ (42 g, 0.28 mol) in water (250 mL). The reaction wasstirred at rt for 6 h, and was then diluted with EtOAc and water. Thelayers were separated and the aqueous phase was extracted with EtOAc(2×). The combined organics were washed with sat aq. NaHSO₃, brine,dried (MgSO₄), and concentrated in vacuo. The crude oil was purified bychromatography on SiO₂ (EtOAc/hex) to afford the title compound as acolorless solid (39.2 g, ˜79% from e). ¹H NMR (MeOD, 400 MHz) δ 4.45 (d,1H), 3.7 (s, 3H), 2.6-2.5 (m, 1H), 2.41-2.23 (m, 2H), 1.7-1.62 (m, 1H),1.55-1.45 (m, 1H), 1.42 (s, 9H), 0.96 (d, 3H).

(2S,3R)-1-tert-Butyl 2-methyl3-methyl-3,4-dihydropyridine-1,2(2H)-dicarboxylate (i)

To the solution of compound h (39.2 g, 0.145 mol) in THE (400 mL) at−78° C. was added LiBEt₃H (1.0 M in THF, 1.1 eq) dropwise. The reactionwas stirred at −78° C. for 2 h, and then quenched with sat. aq NH₄Cl andwarmed to rt and diluted with EtOAc. The layers were separated, and theaqueous layer was extracted with EtOAc (2×). The combined organics werewashed with brine, dried (MgSO₄), and concentrated.

To a solution of the resulting crude colorless oil in CH₂Cl₂ (1 L) at−78° C. was added DIEA (101 mL, 4 eq) followed by the dropwise additionof TFAA (41 mL, 2 eq). The reaction was stirred at −78° C. for 3 h, andthen slowly warmed to rt and monitored for disappearance of sm by tlcanalysis. When the reaction was judged complete, it was cooled to 0° C.and quenched with sat. aq NaHCO₃. The layers were separated. The organiclayer was washed with NaHCO₃, brine, dried (MgSO₄) and concentrated invacuo. Purification on SiO₂ (EtOAc/hex) afforded the title compound as anear colorless oil which solidified (33 g, 89%). ¹H NMR (D₆-DMSO, 400MHz) δ 6.7 (br dd, 1H), 4.85 (dt, 1H), 4.52 (dd, 1H), 3.67 (s, 1.6H),3.63 (s, 1.4H), 2.15-2.06 (m, 1H), 2.02-1.94 (m, 1H), 1.7-1.6 (m, 1H),1.45 (s, 4.5H), 1.4 (s, 4.5H), 1.05 (dd, 3H).

(2S, 3R)-1-tert-Butyl 2-methyl 5, 6-dihydroxy-3-methylpiperidine-1,2-dicarboxylate (j)

To a 0° C. solution of enamide compound i (33 g, 0.13 mol) and NMO (23g, 0.19 mol) in acetone (300 mL) and H₂O (200 mL) was added OSO₄ (4% wtin H₂O, 1 mol %). The reaction was allowed to warm to rt O/N whereuponthe reaction was judged complete by tlc analysis. The reaction wasquenched with sat aq NaHSO₃ and diluted with EtOAc. The layers wereseparated. The aqueous layer was extracted with EtOAc (2×). The combinedorganics were washed with sat aq NaHSO₃, brine, dried (MgSO₄), andconcentrated to give crude diol as a near colorless solid which was usedwithout further purification (35.9 g). 1H NMR (DMSO-d6, 400 MHz) δ 5.86(br s, 1.0H), 5.37 (br s, 1.0H), 4.67 (d, 1.0H), 4.05 (d, 1.0H),3.90-3.83 (m, 1.0H), 3.62 (s, 3.0H), 2.67 (br s, 1.0H), 1.58-1.51 (m,1.0H), 1.41-1.36 (m, 1.0H), 1.35 (s, 9.0H), 0.88 (d, 3.0H) ppm; ESI-MS(m/z): 312.90 [M+Na]+.

(2S, 3R)-1-tert-Butyl 2-methyl3-methyl-5-oxopiperidine-1,2-dicarboxylate (k)

To a solution of crude diol compound j in CHCl₃ (0.8 L) was added p-TsOH(200 mg,). The reaction was warmed to 60° C. and monitored fordisappearance of sm by tlc analysis (1-3 h). The reaction was cooled tort, and washed with sat aq NaHCO₃ (2×), dried (MgSO₄), and concentratedin vacuo. The crude ketone was purified by chromatography on SiO₂(EtOAc/hex) to give the title compound as a pale yellow oil (31.1 g, 88%for 2 steps). ¹H NMR (CDCl₃, 400 MHz) δ 4.8 (br s, 0.6H), 4.6 (br s,0.4H), 4.20-4.10 (m, 2H), 3.83 (s, 3H), 2.60-2.3 (m, 3H), 1.48 (br s,9H). 1.12 (br s, 3H).

(2S, 3R)-1-tert-Butyl 2-methyl5,5-difluoro-3-methylpiperidine-1,2-dicarboxylate (l)

DAST (64 g, 0.4 mol) was added to a solution of compound k (31.1 g, 0.11mol) in CH₂Cl₂ (110 mL) at 0° C. After stirring overnight at RT, thereaction was carefully quenched into a 0° C. mixture of CH₂Cl₂/sat aqNaHCO₃ and then warmed to rt. The layers were separated and the organiclayer was washed with sat aq NaHCO₃, dried (MgSO₄), and concentrated.The crude residue was purified by chromatography on SiO₂ (EtOAc/hex) togive the title compound as a near colorless oil (26.8 g, 79%). ¹H NMR(CDCl₃, 400 MHz) δ 4.9 (br s, 0.6H), 4.65 (br s, 0.4H), 4.33-4.18 (m,1H), 3.75 (s, 3H), 3.7-3.55 (m, 1H), 2.283 (br s, 1H), 2.1-1.86 (m, 2H),1.49 (s, 9H). 1.2 (d, 3H).

(2S, 3R)-Methyl 5, 5-difluoro-3-methylpiperidine-2-carboxylate (m)

To a solution of compound l (10 g, 0.034 mol) in CH₂Cl₂ (150 mL) at 0°C. was added TFA (50 mL). The reaction was allowed to warm to rt andmonitored for disappearance of sm by tlc analysis (3-4 h). Whencomplete, the reaction was concentrated in vacuo to give an oil whichwas used without further purification. ¹H NMR (MeOD, 400 MHz) δ 4.22 (m,1H), 3.9 (s, 3H), 3.42-3.38 (m, 1H), 3.10-3.0 (m, 1H), 2.63-2.55 (m,1H), 1.97-1.70 (m, 4H), 1.03 (d, 3H).

(2S, 3R)-1-Benzyl 2-methyl5,5-difluoro-3-methylpiperidine-1,2-dicarboxylate (n)

To a 0° C. solution of crude compound m in THF/sat aq NaHCO₃ (400 mL,1:1 v/v) was added CbzCl (14.6 g, 0.085 mol). The reaction was allowedto warm to rt O/N, and was then diluted with EtOAc. The layers wereseparated. The aqueous layer was extracted with EtOAc (2×). The combinedorganics were washed with brine, dried (MgSO₄) and concentrated. Thecrude residue was purified by chromatography on SiO₂ (EtOAc/hex) to givethe title compound as a near colorless oil (10.7 g, 96% 2 steps). 1H NMR(CDCl3, 400 MHz) δ 7.5-7.3 (m, 5H), 5.3-5.1 (m, 2H), 5.0-4.9 (m, 0.6H),4.85-4.75 (m, 0.4H, 4.5-4.35 (m, 1H), 3.8-3.8 (m, 3H), 3.7-3.5 (m, 1H),2.4-2.25 (m, 1H), 2.2-1.9 (m, 2H), 1.15-1.0 (m, 3H).

(2S,3R)-1-(Benzyloxycarbonyl)-5,5-difluoro-3-methylpiperidine-2-carboxylicacid (o)

To a 0° C. solution of compound n (10.7 g) in THF (150 mL) was added 1MLiOH (100 mL). The reaction was allowed to warm to rt O/N. The reactionwas diluted with EtOAc, and acidified with 1M HCl until pH˜3. The layerswere separated, and the organic phase was washed with brine, dried(MgSO₄) and concentrated in vacuo to give a near colorless oil. Thecrude acid (9.8 g, 96%) was used without further purification. ¹H NMR(MeOD, 400 MHz) δ 7.4-7.3 (m, 5H), 5.3-5.1 (m, 2H), 4.85-4.75 (m, 1H),4.3-4.2 (m, 1H), 3.78-3.5 (m, 1H), 2.35-2.2 (m, 1H), 2.15-2.02 (m, 1H),2.0-1.85 (m, 1H), 1.15 (t, 3H).

(2S, 3R)-benzyl5,5-difluoro-2-(hydroxymethyl)-3-methylpiperidine-1-carboxylate (p)

To a 0° C. solution of compound o (9.8 g, 0.031 mol) in THF (100 mL) wasadded BH₃/THF (1.0 M, 47 mL). The reaction was allowed to warm to rt andmonitored by reverse-phase HPLC. Additional BH₃/THF (15 mL) was added.After an additional 6 h, sm was consumed by HPLC. The reaction wasquenched with MeOH, and concentrated in vacuo. The crude colorless oilwas taken up in EtOAc and washed with 1M HCl (2×), brine, dried (MgSO₄)and concentrated to give the title compound (8.8 g, 94%) as a colorlessoil, which was used without further purification. ESI-MS (m/z): 300.29[M+1]⁺. 1H NMR (D6-DMSO, 400 MHz) δ 7.4-7.3 (m, 5H), 5.2-5.1 (q, 2H),4.85-4.7 (m, 1H), 4.5 (d, 0.36H), 4.25-4.1 (m, 1.64H), 3.8-3.7 (m, 1H),3.6-3.5 (m, 1H), 3.5-3.2 (m, 1H), 2.1-1.9 (m, 2H), 1.0 (br s, 3H).

(2S, 3R)-benzyl2-((1,3-dioxoisoindolin-2-yl)methyl)-5,5-difluoro-3-methylpiperidine-1-carboxylate(q)

To a solution of crude compound p (8.8 g, 0.03 mol) in dry toluene (100mL) was added ADDP (14.9 g, 0.059 mol) followed by PBu₃ (17.9 g, 0.089mol). After stirring at rt for 45 min, phthalimide (6.5 g, 0.044 mol)was added and the reaction mixture was warmed to 80° C. O/N. After 12 h,starting alcohol compound p was consumed as judged by reverse-phaseanalytical HPLC analysis. The reaction mixture was cooled to rt,filtered through a SiO₂ pad (washing with toluene), and concentrated invacuo. The resulting crude oil was purified by chromatography on SiO₂(EtOAc/hex) to afford the title compound (11 g, ˜87%) contaminated byphthalimide. [The phthalimide could be removed by dissolving in EtOAcand washing with 1M NaOH, but it is also removed in the next step.]ESI-MS (m/z): 429.40 [M+1]⁺. ¹H NMR (D₆-DMSO, 400 MHz) δ 7.9-7.8 (m,4H), 7.35-7.2 (m, 2H), 7.18-7.1 (m, 1H), 7.1-7.0 (m, 1H), 6.9 (d, 1H),4.85-4.7 (m, 1.5H), 4.5 (d, 1H), 4.48-4.35 (m, 0.5H), 4.25-4.1 (m, 2H),3.7-3.45 (m, 2H), 2.25-2.0 (m, 3H), 1.1 (t, 3H).

(2S,3R)-Benzyl2-(aminomethyl)-5,5-difluoro-3-methylpiperidine-1-carboxylate (r)

Hydrazine (6.2 mL, 5 eq) was added to a solution of compound q (11 g, 23mmol) in MeOH (150 mL). The reaction was warmed to 80° C. for 2 hwherein sm was consumed as judged by reverse-phase analytical HPLCanalysis. The reaction mixture was cooled and concentrated in vacuo. Thecrude residue was taken up in EtOAc and washed with sat aq NaHCO₃ (4×),brine, dried (MgSO₄), and concentrated in vacuo to give the titlecompound (6.9 g, 90%) as a pale yellow oil which was used withoutfurther purification. %). ESI-MS (m/z): 299.3 [M+1]⁺.

(2S,3R)-benzyl5,5-difluoro-3-methyl-2-(((5-(trifluoromethyl)pyrimidin-2-yl)amino)methyl)piperidine-1-carboxylate(s)

(Synthetic procedure is given for the compound in which ArX is2-Cl-5-CF₃-pyrimidine.) To a mixture of the crude amine compound r (2.2g, 7.4 mmol) and K₂CO₃ (2 g, 14.8 mmol) in DMF (20 mL) was added2-Cl-5-CF₃-pyrimidine (2 g, 11.1 mmol). The reaction was warmed to 80°C. for 2 h wherein the starting material was judged consumed asindicated by reverse-phase analytical HPLC. The reaction was cooled, anddiluted with EtOAc, and water. The layers were separated, and theorganic phase was washed with water (3×), brine, dried (MgSO₄) andconcentrated. The crude residue was purified by chromatography on SiO₂(EtOAc/hex) to give the title compound as a pale yellow solid (2.4 g,75%). ESI-MS (m/z): 445.4 [M+1]⁺.

(2S,3R)-5,5-difluoro-3-methyl-2-(((5-(trifluoromethyl)pyrimidin-2-yl)amino)methyl)piperidin-1-iumbromide (t)

(Synthetic procedure is given for the compound in which Ar is5-CF₃-pyrimidine.) Carbamate compound s (2.4 g, 5.4 mmol) was added to30% HBr in HOAc (15 mL). The reaction was stirred at rt (1-3 h) until smwas consumed as judged by HPLC analysis. The reaction was concentratedin vacuo to give the title compound as a pale yellow foam (2.1 g, ˜100%)and was used without purification. ¹H NMR (D₆-DMSO, 400 MHz) δ 9.7 (brs, 1H), 9.15 (br s, 1H), 8.7 (s, 2H), 8.15 (t, 1H), 3.92-3.7 (m, 1H),3.7-3.5 (m, 4H), 2.4-2.05 (m, 3H), 1.1 (d, 3H).

Compound (u)

To a solution of compound t, HATU (1.5 eq), and a carboxylic acid (1.2eq) in DMF was added DIEA (3 eq). When the starting amine was consumedas judged by HPLC (anywhere from 30 min to 24 h depending on the acidused), the reaction was diluted with EtOAc, and washed with sat aqNaHCO₃, brine, dried (MgSO₄), and concentrated. The crude residue waspurified by chromatography on SiO₂ (EtOAc/hex) to give the desiredcompound.

Exemplary Carboxylic Acids Include Compounds aa-cv Compound aa:4-(5-fluoropyrimidin-2-yl)-1-methyl-1H-pyrazole-3-carboxylic acid

Step 1: ethyl 4-iodo-1H-pyrazole-3-carboxylate

To a solution of ethyl 1H-pyrazole-3-carboxylate (2 g, 14.3 mol, 1.0 eq)and I₂ (3.6 g, 14.3 mmol, 1.0 eq) in ACN (14 mL) was added CAN (1.6 g,2.86 mmol, 0.2 eq) at RT. The reaction mixture was stirred at RTovernight, and was monitored by reverse-phase analytical HPLC. Whenstarting material was consumed, the reaction mixture was concentrated invacuo to afford a crude solid which was slowly poured into a saturatedNa₂S₂O₃ solution and H₂O (1:1) with stirring. The light-yellowsuspension was filtered and the filter cake was washed with H₂O. Theresulting near colorless solid was dried under vacuum and used withoutfurther purification. ¹H NMR (400 MHz, CDCl₃) δ 7.86 (s, 1H), 4.46 (q,J=7.2 Hz, 2H), 1.45 (t, J=7.2 Hz, 3H).

Step 2: 4-iodo-1-methyl-1H-pyrazole-3-carboxylic acid

NaH (60% dispersion in mineral oil, 0.72 g, 18 mmol, 1.2 eq) was addedin portions to a mixture of ethyl 4-iodo-1H-pyrazole-3-carboxylate (4.2g, 15 mmol, 1.0 eq) and anhydrous THE (15 mL) at 0° C. Once addition ofNaH was complete, the mixture was stirred for an additional 30 min at 0°C. and 1 h at RT. The mixture was re-cooled to 0° C. and then MeI (1.0mL, 16.5 mmol, 1.1 eq) was added. When the reaction mixture solidified,the cold bath was removed and the mixture was maintained at RT for 1 h.When the starting material was consumed as judged by analytical HPLC,H₂O (0.5 mL) was added slowly to quench the reaction and then NaOHsolution (2 M, 1.0 eq) was added slowly with stirring. The mixture wasstirred at rt until hydrolysis of the ester was complete (˜1-2 h). Thelight-yellow suspension was filtered and the resulting yellow solid wascollected. The filtrate was concentrated in vacuo and then washed withhexanes to remove the mineral oil. The resulting aqueous layer and solidwere combined and acidified with 6N HCl to pH 1-2. The aqueous wasextracted with EtOAc (3×). The combined organics were washed with brine,dried (Na₂SO₄), and concentrated to afford the title acid as a paleyellow solid that was used without further purification.

Step 3: tert-butyl 4-iodo-1-methyl-1H-pyrazole-3-carboxylate

To a mixture of crude 4-iodo-1-methyl-1H-pyrazole-3-carboxylic acid (3.1g, 12.5 mmol) and THE (15 mL) was added tert-BuOH (1.2 mL, 12.5 mol, 1.0eq) and DMAP (0.30 g, 2.5 mmol, 0.2 eq) followed by (Boc)₂O (3.5 g, 16.2mol, 1.3 eq) in portions. The mixture was stirred overnight at RT, andthe reaction was monitored by analytical HPLC. When the acid wasconsumed, the reaction was concentrated in vacuo to afford a crude solidwhich was dissolved in EtOAc. The resulting organic solution was washedwith 2N HCl (3×), H₂O, brine and dried (Na₂SO₄). The solvent was removedin vacuo to obtain the title compound as a pale yellow solid which wasused without further purification. ¹H NMR (400 MHz, CDCl₃) δ 7.50 (s,1H), 3.96 (s, 3H), 1.65 (s, 9H).

Step 4: (3-(tert-butoxycarbonyl)-1-methyl-1H-pyrazol-4-yl)boronic acid

To a solution of crude tert-butyl4-iodo-1-methyl-1H-pyrazole-3-carboxylate (1.6 g, 5.1 mmol, 1.0 eq) andB(Oi-Pr)₃ (1.8 mL, 7.7 mmol, 1.5 eq) in anhydrous THE (6 mL) at −78° C.under argon, was added n-BuLi (2.5M, 3.6 mL, 9.2 mmol) dropwise. Thereaction was stirred at −78° C. and monitored by analytical HPLC fordisappearance of starting material. When complete (1-2 h), H₂O (5 mL)was added slowly to quench the reaction and the resulting mixture wasslowly warmed to RT. The mixture was then slowly poured into 2N HClsolution to bring the pH 2˜3. The reaction mixture was diluted withEtOAc and the layers were separated. The aqueous layer was extractedwith EtOAc (2×). The combined organic extracts were washed with brine,dried (Na₂SO₄) and concentrated to provide the crude boronic acid as abrown solid that was used without further purification.

Step 5: tert-butyl4-(5-fluoropyrimidin-2-yl)-1-methyl-1H-pyrazole-3-carboxylate

To the crude boronic acid obtained from previous step was added DMF/H₂O(5:1, 9 mL), K₂CO₃ (1.0 g, 7.7 mmol, 1.5 eq) and2-chloro-5-fluoropyrimidine (0.76 mL, 6.1 mmol, 1.2 eq). The mixture wasdegassed, and then Pd(PPh₃)₄ (0.18 g, 0.13 mmol, 0.025 eq) was added.The mixture was degassed and then heated overnight in an 80° C. oil bathunder argon. The completion of the reaction was monitored by analyticalHPLC. When complete, the reaction mixture was cooled to RT, and filteredthrough a celite pad to remove K₂CO₃ and Pd. The filter cake was washedwith toluene. The filtrate was diluted with toluene was washed with H₂Oand the layers were separated. The aqueous layer was extracted withtoluene (2×). The combined organic layers were dried (Na₂SO₄) andconcentrated to provide the crude as an amber oil that was used withoutfurther purification. ESI-MS (m/z): 278.58 [M+1]⁺.

Step 6: 4-(5-fluoropyrimidin-2-yl)-1-methyl-1H-pyrazole-3-carboxylicacid

To a solution of the crude tert-butyl ester obtained from the previousstep in DCM (2 mL) was added TFA (1.5 mL). The reaction mixture wasstirred at RT monitoring by analytical HPLC for disappearance ofstarting material (3-4 h). When complete, the reaction was concentratedin vacuo to obtain the crude as a dark oil. Toluene was added and thereaction was concentrated in vacuo to remove residual TFA. The crude oilwas cooled to 0° C. and MeOH was added with stirring. A suspensionquickly formed and was stirred for an additional 1 h. The suspension wasfiltered and washed with cold MeOH to give the title compound as a nearcolorless solid. ¹H NMR (400 MHz, d-DMSO) δ 14.80 (broad, 1H), 9.10 (s,2H), 8.55 (s, 1H), 4.00 (s, 3H); ESI-MS (m/z): 222.79 [M+1]⁺.

Compound ab:4-(5-chloropyrimidin-2-yl)-1-methyl-1H-pyrazole-3-carboxylic acid

Step 1: methyl 4-bromo-1-methyl-1H-pyrazole-3-carboxylate

NaH (60% dispersion in mineral oil, 11.3 g, 282 mmol, 3.0 eq) was addedin portions to a mixture of 4-bromo-1H-pyrazole-3-carboxylic acid (18 g,94.2 mmol, 1.0 eq) in) anhydrous DMF (200 mL) at 0° C. under argonprotection. Once addition of NaH was complete, the mixture was stirredfor an additional 30 min at 0° C. and 1 h at RT. The mixture wasre-cooled to 0° C. and then MeI (24 mL, 377 mmol, 4.0 eq) was added. Thereaction mixture was diluted with EtOAc and washed with Sat'd NaHCO₃,brine and dried over Na₂SO₄. The organic layers were concentrated toprovide the crude as solid that was used without further purification.¹H NMR (400 MHz, CDCl₃) δ 7.87 (s, 1H), 3.96 (s, 3H), 3.88 (s, 3H).

Step 2: (3-(methoxycarbonyl)-1-methyl-1H-pyrazol-4-yl)boronic acid

(3-(methoxycarbonyl)-1-methyl-1H-pyrazol-4-yl)boronic acid was preparedfollowing the same general protocol as described for(3-(tert-butoxycarbonyl)-1-methyl-1H-pyrazol-4-yl)boronic acid usingmethyl 4-bromo-1-methyl-1H-pyrazole-3-carboxylate.

Step 3: methyl4-(5-chloropyrimidin-2-yl)-1-methyl-1H-pyrazole-3-carboxylate

To the crude boronic acid (0.86 g, 4.14 mmol) obtained from previousstep was added dioxane/H₂O (4:1, 42 mL), K₂CO₃ (1.714 g, 12.41 mmol, 3.0eq) and 2,5-dichloropyrimidine (0.74 g, 4.14 mmol, 1.2 eq). The mixturewas degassed, and then Pd(PPh₃)₄ (0.48 g, 0.41 mmol, 0.1 eq) was added.The mixture was degassed and then heated overnight in an 80° C. oil bathunder argon. The completion of the reaction was monitored by analyticalHPLC. When complete, the reaction mixture was cooled to RT, and filteredthrough a celite pad to remove K₂CO₃ and Pd. The filter cake was washedwith EtOAc. The filtrate was diluted with EtOAc and washed with H₂O andthe layers were separated. The aqueous layer was extracted with EtOAc(2×). The combined organic layers were concentrated to provide the crudewhich was purified by column chromatography on silica gel to obtain thedesired product. ESI-MS (m/z): 252.97 [M+1]⁺.

Step 4: 4-(5-chloropyrimidin-2-yl)-1-methyl-1H-pyrazole-3-carboxylicacid

Methyl 4-(5-chloropyrimidin-2-yl)-1-methyl-1H-pyrazole-3-carboxylate(0.22 g, 0.873 mmol) in THE (5 mL) was added NaOH (1.0 M, 4 mL, 5.0 eq).The completion of the reaction was monitored by analytical HPLC. Whencomplete, the reaction mixture was acidified to pH˜2. The solvent wasremoved in vacuo. The crude was extracted with MeOH. The solvent wasremoved and the obtained acid was dried in vacuum for next step with nofurther purification. ESI-MS (m/z): 239.03 [M+1]⁺.

Compound ac:1-methyl-4-(4-methylpyrimidin-2-yl)-1H-pyrazole-3-carboxylic acid

The title compound was synthesized following the same general protocolas described for4-(5-chloropyrimidin-2-yl)-1-methyl-1H-pyrazole-3-carboxylic acid using(3-(methoxycarbonyl)-1-methyl-1H-pyrazol-4-yl)boronic acid and2-chloro-4-methylpyrimidine. ESI-MS (m/z): 219.0 [M+1]⁺.

Compound ad:1-methyl-4-(5-methylpyrimidin-2-yl)-1H-pyrazole-3-carboxylic acid

The title compound was synthesized following the same general protocolas described for4-(5-chloropyrimidin-2-yl)-1-methyl-1H-pyrazole-3-carboxylic acid using(3-(methoxycarbonyl)-1-methyl-1H-pyrazol-4-yl)boronic acid and2-chloro-5-methylpyrimidine. ESI-MS (m/z): 219.0 [M+1]⁺.

Compound ae:1-methyl-4-(5-(trifluoromethyl)pyrimidin-2-yl)-1H-pyrazole-3-carboxylicacid

The title compound was synthesized following t e same genera protocol asdescribed for4-(5-chloropyrimidin-2-yl)-1-methyl-1H-pyrazole-3-carboxylic acid using(3-(methoxycarbonyl)-1-methyl-1H-pyrazol-4-yl)boronic acid and2-chloro-5-(trifluoromethyl)pyrimidine. ESI-MS (m/z): 272.95 [M+1]⁺.

Compound af: 1-methyl-4-(pyrimidin-2-yl)-1H-pyrazole-3-carboxylic acid

Step 1: methyl 1-methyl-4-(pyrimidin-2-yl)-1H-pyrazole-3-carboxylate

A mixture of methyl 4-bromo-1-methyl-1H-pyrazole-3-carboxylate (1.5 g,6.84 mmol, 1.0 eq), 2-(tributylstannyl)pyrimidine (2.4 mL, 7.52 mmol,1.1 eq), CsF (2.1 g, 13.67 mmol, 2.0 eq), Pd(PPh₃)₄ (0.79 g, 0.68 mmol,0.1 eq) and CuI (0.13 g, 0.68 mmol, 0.1 eq) in DMF (120 mL) was degassedfor 10 min and then heated overnight at oil bath at 110° C. Thecompletion of the reaction was monitored by analytical HPLC. Whencomplete, the mixture was cooled and concentrated. The crude wasdissolved with EtOAc and washed with Sat'd NaHCO₃ and brine. The solventwas removed to obtain the crude, which was purified by silica gel toobtain the desired product. ESI-MS (m/z): 218.99 [M+1]⁺.

Step 2: 1-methyl-4-(pyrimidin-2-yl)-1H-pyrazole-3-carboxylic acid

The acid was prepared following the same general protocol as describedfor 4-(5-chloropyrimidin-2-yl)-1-methyl-1H-pyrazole-3-carboxylic acidusing methyl 1-methyl-4-(pyrimidin-2-yl)-1H-pyrazole-3-carboxylate.ESI-MS (m/z): 204.96 [M+1]⁺.

Compound ag: 1-methyl-4-(pyridin-2-yl)-1H-pyrazole-3-carboxylic acid

The title compound was made following the same general protocol asdescribed for Compound af using methyl4-bromo-1-methyl-1H-pyrazole-3-carboxylate and2-(tributylstannyl)pyridine. ESI-MS (m/z): 203.93 [M+1]⁺.

Compound ah: 4-(5-fluoropyridin-2-yl)-1-methyl-1H-pyrazole-3-carboxylicacid

Step 1: General Procedure for Stannane Synthesis:5-fluoro-2-(tributylstannyl)pyridine

To a solution of 2-bromo-5-fluoropyridine (2.42 g, 13.75 mmol, 1.0 eq)in THE (30 mL) was added n-BuLi (2.5 M in hexane, 5.5 mL, 13.75 mmol,1.0 eq) and the mixture was stirred at −78° C. for 30 min under nitrogenatmosphere. n-Bu₃SnCl (4 mL, 14.58 mmol, 1.05 eq) was added and themixture was stirred at the same temperature for another 2 h. Saturatedammonium chloride solution (150 mL) was added to the solution andextracted with ethyl acetate (150 mL×3). The combined organic layerswere dried over Na₂SO₄, filtered and concentrated in vacuo. The crude5-fluoro-2-(tributylstannyl)pyridine as a yellow oil was used withoutfurther purification.

Step 2: 4-(5-fluoropyridin-2-yl)-1-methyl-1H-pyrazole-3-carboxylic acid

The title compound was made following the same general protocol asdescribed for Compound af using methyl4-bromo-1-methyl-1H-pyrazole-3-carboxylate and5-fluoro-2-(tributylstannyl)pyridine. ESI-MS (m/z): 221.95 [M+1]⁺.

Compound ai: 4-(3-fluoropyridin-2-yl)-1-methyl-1H-pyrazole-3-carboxylicacid

The title compound was made following the same general protocol asdescribed for Compound af using methyl4-bromo-1-methyl-1H-pyrazole-3-carboxylate and3-fluoro-2-(tributylstannyl)pyridine ESI-MS (m/z): 221.95 [M+1]⁺.

Compound aj: 1-methyl-4-(3-methylpyridin-2-yl)-1H-pyrazole-3-carboxylicacid

The title compound was made following the same general protocol asdescribed for Compound af using methyl4-bromo-1-methyl-1H-pyrazole-3-carboxylate and3-methyl-2-(tributylstannyl)pyridine. ESI-MS (m/z): 217.92 [M+1]⁺.

Compound ak: 1-methyl-4-(4-methylpyridin-2-yl)-1H-pyrazole-3-carboxylicacid

The title compound was made following the same general protocol asdescribed for Compound af using methyl4-bromo-1-methyl-1H-pyrazole-3-carboxylate and4-methyl-2-(tributylstannyl)pyridine. ESI-MS (m/z): 217.92 [M+1]⁺.

Compound ak: 1-methyl-4-(5-methylpyridin-2-yl)-1H-pyrazole-3-carboxylicacid

The title compound was made following the same general protocol asdescribed for Compound af using methyl4-bromo-1-methyl-1H-pyrazole-3-carboxylate and5-methyl-2-(tributylstannyl)pyridine. ESI-MS (m/z): 217.92 [M+1]⁺.

Compound am: 1-methyl-4-(6-methylpyridin-2-yl)-1H-pyrazole-3-carboxylicacid

The title compound was made following the same general protocol asdescribed for Compound af using methyl4-bromo-1-methyl-1H-pyrazole-3-carboxylate and2-methyl-6-(tributylstannyl)pyridine. ESI-MS (m/z): 217.92 [M+1]⁺.

Compound an: 4-(6-methoxypyridin-2-yl)-1-methyl-1H-pyrazole-3-carboxylicacid

The title compound was made following the same general protocol asdescribed for Compound af using methyl4-bromo-1-methyl-1H-pyrazole-3-carboxylate and2-methoxy-6-(tributylstannyl)pyridine. ESI-MS (m/z): 233.94 [M+1]⁺.

Compound ao: 1-methyl-4-(pyridin-3-yl)-1H-pyrazole-3-carboxylic acid

Step 1: methyl 1-methyl-4-(pyridin-3-yl)-1H-pyrazole-3-carboxylate

The mixture of methyl 4-bromo-1-methyl-1H-pyrazole-3-carboxylate (0.15g, 0.684 mmol, 1.0 eq), pyridin-3-ylboronic acid (0.11 g, 0.89 mmol, 1.3eq) and K₂CO₃ (0.28 g, 2.05 mmol, 3.0 eq) in dioxane/H₂O (4:1, 3 mL wasdegassed, and then Pd(PPh₃)₄ (0.08 g, 0.07 mmol, 0.1 eq) was added. Themixture was degassed and then heated for 30 min at 120° C. in amicrowave reactor. The completion of the reaction was monitored byanalytical HPLC. When complete, the reaction mixture was cooled to RTand diluted with EtOAc and washed with H₂O and the layers wereseparated. The aqueous layer was extracted with EtOAc (2×). The combinedorganic layers were concentrated to provide the crude which was purifiedby column chromatography on silica gel to obtain the desired product.ESI-MS (m/z): 218.08 [M+1]⁺.

Step 2: 1-methyl-4-(pyridin-3-yl)-1H-pyrazole-3-carboxylic acid

The acid was prepared following the same general protocol as describedfor 4-(5-chloropyrimidin-2-yl)-1-methyl-1H-pyrazole-3-carboxylic acidusing methyl 1-methyl-4-(pyrimidin-2-yl)-1H-pyrazole-3-carboxylate.ESI-MS (m/z): 203.93 [M+1]⁺.

Compound ap: 4-(2-fluorophenyl)-1-methyl-1H-pyrazole-3-carboxylic acid

The title compound was made following the same general protocol asdescribed for Compound ao using methyl4-bromo-1-methyl-1H-pyrazole-3-carboxylate and (2-fluorophenyl)boronicacid ESI-MS (m/z): 220.84 [M+1]⁺.

Compound aq: 4-(3-fluorophenyl)-1-methyl-1H-pyrazole-3-carboxylic acid

The title compound was made following the same general protocol asdescribed for Compound ao using methyl4-bromo-1-methyl-1H-pyrazole-3-carboxylate and (3-fluorophenyl)boronicacid. ESI-MS (m/z): 220.84 [M+1]⁺.

Compound ar: 1-methyl-4-(p-tolyl)-1H-pyrazole-3-carboxylic acid

The title compound was made following the same general protocol asdescribed for Compound ao using methyl4-bromo-1-methyl-1H-pyrazole-3-carboxylate and p-tolylboronic acid.ESI-MS (m/z): 216.83 [M+1]⁺.

Compound as: 1-methyl-4-(o-tolyl)-1H-pyrazole-3-carboxylic acid

The title compound was made following the same general protocol asdescribed for Compound ao using methyl4-bromo-1-methyl-1H-pyrazole-3-carboxylate and o-tolylboronic acidESI-MS (m/z): 216.83 [M+1]⁺.

Compound at: 1-methyl-4-(m-tolyl)-1H-pyrazole-3-carboxylic acid

The title compound was made following the same general protocol asdescribed for Compound ao using methyl4-bromo-1-methyl-1H-pyrazole-3-carboxylate and m-tolylboronic acid.ESI-MS (m/z): 216.83 [M+1]⁺.

Compound au: 4-(3-methoxyphenyl)-1-methyl-1H-pyrazole-3-carboxylic acid

The title compound was made following the same general protocol asdescribed for Compound ao using methyl4-bromo-1-methyl-1H-pyrazole-3-carboxylate and (3-methoxyphenyl)boronicacid. ESI-MS (m/z): 232.84 [M+1]⁺.

Compound av: 4-(4-methoxyphenyl)-1-methyl-1H-pyrazole-3-carboxylic acid

The title compound was made following the same general protocol asdescribed for Compound ao using methyl4-bromo-1-methyl-1H-pyrazole-3-carboxylate and (4-methoxyphenyl)boronicacid. ESI-MS (m/z): 232.84 [M+1]⁺.

Compound aw: 4-(4-chlorophenyl)-1-methyl-1H-pyrazole-3-carboxylic acid

The title compound was made following the same general protocol asdescribed for Compound ao using methyl4-bromo-1-methyl-1H-pyrazole-3-carboxylate and (4-chlorophenyl)boronicacid. ESI-MS (m/z): 236.86 [M+1]⁺.

Compound ax: 1-methyl-4-(6-methylpyridin-3-yl)-1H-pyrazole-3-carboxylicacid

The title compound was made following the same general protocol asdescribed for Compound ao using methyl4-bromo-1-methyl-1H-pyrazole-3-carboxylate and(6-methylpyridin-3-yl)boronic acid. ESI-MS (m/z): 217.92 [M+1]⁺.

Compound ay: 1,5-dimethyl-4-(pyrimidin-2-yl)-1H-pyrazole-3-carboxylicacid

Step 1: tert-butyl 4-bromo-1,5-dimethyl-1H-pyrazole-3-carboxylate

To a mixture of 4-bromo-1,5-dimethyl-1H-pyrazole-3-carboxylic acid (1.0g, 4.56 mmol, 1.0 eq) and t-BuOH (0.87 mL, 9.12 mmol, 2.0 eq) in DCM (15mL) was added DMAP (0.11 g, 0.91 mmol, 0.2 eq) and DCC (1.13 g, 5.47mmol, 1.2 eq). The completion of the reaction was monitored byanalytical HPLC. When complete, the reaction mixture was diluted withDCM and washed with 0.5 N HCl, water, Sat'd NaHCO₃ and brine. Thecombined organic layers were concentrated to provide the crude which waspurified by column chromatography on silica gel to obtain the desiredproduct. ¹H NMR (400 MHz, CDCl₃) δ 3.95 (s, 3H), 2.27 (s, 3H), 1.65 (s,9H).

Step 2: tert-butyl1,5-dimethyl-4-(pyrimidin-2-yl)-1H-pyrazole-3-carboxylate

The title compound was prepared following the same general protocol asdescribed for Compound sg using tert-butyl4-bromo-1,5-dimethyl-1H-pyrazole-3-carboxylate and2-(tributylstannyl)pyrimidine. ESI-MS (m/z): 274.99 [M+1]⁺.

Step 3: 1,5-dimethyl-4-(pyrimidin-2-yl)-1H-pyrazole-3-carboxylic acid

The acid was prepared following the same general protocol as describedfor Compound af using tert-butyl1,5-dimethyl-4-(pyrimidin-2-yl)-1H-pyrazole-3-carboxylate. ESI-MS (m/z):218.84 [M+1]⁺.

Compound az: 5-(5-fluoropyridin-2-yl)-2-methylthiazole-4-carboxylic acid

Step 1: 5-fluoro-2-(tributylstannyl)pyridine

To a solution of 2-bromo-5-fluoropyridine (2.42 g, 13.75 mmol, 1.0 eq)in THE (30 mL) was added n-BuLi (2.5 M in hexane, 5.5 mL, 13.75 mmol,1.0 eq) and the mixture was stirred at −78° C. for 30 min under nitrogenatmosphere. n-Bu₃SnCl (4 mL, 14.58 mmol, 1.05 eq) was added and themixture was stirred at the same temperature for another 2 h. Saturatedammonium chloride solution (150 mL) was added to the solution andextracted with ethyl acetate (150 mL×3). The combined organic layerswere dried over Na₂SO₄, filtered and concentrated in vacuo. The crude5-fluoro-2-(tributylstannyl)pyridine as a yellow oil was used withoutfurther purification.

Step 2: methyl 5-(5-fluoropyridin-2-yl)-2-methylthiazole-4-carboxylate

A mixture of methyl 5-bromo-2-methylthiazole-4-carboxylate (0.15 g,0.635 mmol, 1.0 eq), 5-fluoro-2-(tributylstannyl)pyridine (0.368 g, 0.95mmol, 1.5 eq), CsF (0.193 g, 13.67 mmol, 2.0 eq), Pd(PPh₃)₄ (0.073 g,0.064 mmol, 0.1 eq) and CuI (0.012 g, 0.064 mmol, 0.1 eq) in DMF (4 mL)was degassed for 5 min and then heated for 1 h at 120° C. in a microwavereactor. The completion of the reaction was monitored by analyticalHPLC. When complete, the mixture was cooled and concentrated. The crudewas dissolved with EtOAc and washed with Sat'd NaHCO₃ and brine. Thesolvent was removed to obtain the crude, which was purified by silicagel to obtain the desired product. ESI-MS (m/z): 253.07 [M+1]⁺.

Step 3: 5-(5-fluoropyridin-2-yl)-2-methylthiazole-4-carboxylic acid

methyl 5-(5-fluoropyridin-2-yl)-2-methylthiazole-4-carboxylate (0.16 g,0.64 mmol, 1.0 eq) in THE (5 mL) was added NaOH (1M, 3 mL, 5.0 eq). Themixture was heat for 2 h at 100° C. at oil bath. The completion of thereaction was monitored by analytical HPLC. When complete, the reactionmixture was acidified to pH˜2. The solvent was removed in vacuo. Thecrude was purified by silica gel to obtain the desired acid. ESI-MS(m/z): 238.82 [M+1]⁺.

Compound ba: 5-(4-fluoropyridin-2-yl)-2-methylthiazole-4-carboxylic acid

The acid was prepared following the same general protocol as describedfor 5-(5-fluoropyridin-2-yl)-2-methylthiazole-4-carboxylic acid using2-bromo-4-fluoropyridine in Step 1. ESI-MS (m/z): 238.82 [M+1]⁺.

Compound bb: 5-(5-methoxypyridin-2-yl)-2-methylthiazole-4-carboxylicacid

The acid was prepared following the same general protocol as describedfor 5-(5-fluoropyridin-2-yl)-2-methylthiazole-4-carboxylic acid using2-bromo-5-methoxypyridine in Step 1. ESI-MS (m/z): 250.81 [M+1]⁺.

Compound bc: 5-(6-methoxypyridin-2-yl)-2-methylthiazole-4-carboxylicacid

The acid was prepared following the same general protocol as describedfor 5-(5-fluoropyridin-2-yl)-2-methylthiazole-4-carboxylic acid using2-bromo-6-methoxypyridine in Step 1. ESI-MS (m/z): 250.81 [M+1]⁺.

Compound bd: 2-methyl-5-(3-methylpyridin-2-yl)thiazole-4-carboxylic acid

The acid was prepared following the same general protocol as describedfor 5-(5-fluoropyridin-2-yl)-2-methylthiazole-4-carboxylic acid using2-bromo-3-methylpyridine in Step 1. ESI-MS (m/z): 234.79 [M+1]⁺.

Compound be: 2-methyl-5-(5-methylpyridin-2-yl)thiazole-4-carboxylic acid

The acid was prepared following the same general protocol as describedfor 5-(5-fluoropyridin-2-yl)-2-methylthiazole-4-carboxylic acid using2-bromo-5-methylpyridine in Step 1. ESI-MS (m/z): 234.79 [M+1]⁺.

Compound bf: 2-methyl-5-(6-methylpyridin-2-yl)thiazole-4-carboxylic acid

The acid was prepared following the same general protocol as describedfor 5-(5-fluoropyridin-2-yl)-2-methylthiazole-4-carboxylic acid using2-bromo-6-methylpyridine in Step 1. ESI-MS (m/z): 234.79 [M+1]⁺.

Compound bg: 2-methyl-5-(4-methylpyridin-2-yl)thiazole-4-carboxylic acid

The acid was prepared following the same general protocol as describedfor 5-(5-fluoropyridin-2-yl)-2-methylthiazole-4-carboxylic acid using2-bromo-4-methylpyridine in Step 1. ESI-MS (m/z): 234.79 [M+1]⁺.

Compound bh: 2-methyl-5-(pyridin-2-yl)thiazole-4-carboxylic acid

The acid was prepared following the same general protocol as describedfor 5-(5-fluoropyridin-2-yl)-2-methylthiazole-4-carboxylic acid using2-(tributylstannyl)pyridine in Step 2. ESI-MS (m/z): 220.82 [M+1]⁺.

Compound bi: 2-methyl-5-(pyrimidin-2-yl)thiazole-4-carboxylic acid

The acid was prepared following the same general protocol as describedfor 5-(5-fluoropyridin-2-yl)-2-methylthiazole-4-carboxylic acid using2-(tributylstannyl)pyrimidine in Step 1. ESI-MS (m/z): 221.26 [M+1]⁺.

Compound bj: 5-methyl-2-(pyridin-2-yl)thiophene-3-carboxylic acid

The acid was prepared following the same general protocol as describedfor 5-(5-fluoropyridin-2-yl)-2-methylthiazole-4-carboxylic acid inCompound az using 2-(tributylstannyl)pyridine and ethyl2-bromo-5-methylthiophene-3-carboxylate in Step 2. ESI-MS (m/z): 219.94[M+1]⁺.

Compound bk: 2-methyl-5-(pyridin-2-yl)oxazole-4-carboxylic acid

Step 1: ethyl 5-bromo-2-methyloxazole-4-carboxylate

A mixture of tert-butyl nitrite (1.25 mL, 10.50 mmol, 2.0 eq) and CuBr₂(1.76 g, 7.87 mmol, 1.5 eq) in acetonitrile (15 mL) was stirred at 0° C.and a solution of ethyl 5-amino-2-methyloxazole-4-carboxylate (0.89 g,5.248 mmol, 1.0 eq) in acetonitrile (20 mL) was added dropwise. Thereaction mixture was stirred overnight at RT. The mixture was dilutedwith EtOAc, washed with water and brine, and concentrated in vacuo. Thecrude was purified by chromatography on silica gel to obtain the desiredproduct.

Step 2: 2-methyl-5-(pyridin-2-yl)oxazole-4-carboxylic acid

The acid was prepared following the same general protocol as describedfor 5-(5-fluoropyridin-2-yl)-2-methylthiazole-4-carboxylic acid inCompound az using 2-(tributylstannyl)pyridine and ethyl5-bromo-2-methyloxazole-4-carboxylate in Step 1. ESI-MS (m/z): 204.93[M+1]⁺.

Compound bl: 1-methyl-3-(pyridin-2-yl)-1H-pyrazole-4-carboxylic acid

The acid was prepared following the same general protocol as describedfor 5-(5-fluoropyridin-2-yl)-2-methylthiazole-4-carboxylic acid inCompound az using 2-(tributylstannyl)pyridine and ethyl3-bromo-1-methyl-1H-pyrazole-4-carboxylate in Step 1. ESI-MS (m/z):203.93 [M+1]⁺.

Compound bm: 1-methyl-5-(pyridin-2-yl)-1H-pyrazole-4-carboxylic acid

The acid was prepared following the same general protocol as describedfor 5-(5-fluoropyridin-2-yl)-2-methylthiazole-4-carboxylic acid inCompound az using 2-(tributylstannyl)pyridine and ethyl5-bromo-1-methyl-1H-pyrazole-4-carboxylate in Step 1. ESI-MS (m/z):203.93 [M+1]⁺.

Compound bn: 4-cyano-4′-fluoro-[1,1′-biphenyl]-2-carboxylic acid

The mixture of 2-bromo-5-cyanobenzoic acid (0.2 g, 0.89 mmol, 1.0 eq),2-(4-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.39 g, 1.77mmol, 2.0 eq) and K₂CO₃ (0.37 g, 2.655 mmol, 3.0 eq) in DMF (4.5 Ml) wasdegassed, and then Pd(dppf)Cl₂ (0.07 g, 0.09 mmol, 0.1 eq) was added.The mixture was degassed and then heated for 2 h at 120° C. in amicrowave reactor. The completion of the reaction was monitored byanalytical HPLC. When complete, the reaction mixture was cooled to RTand acidified to pH5. The mixture was concentrated to provide the crudewhich was purified by column chromatography on silica gel to obtain thedesired product. ¹H NMR (400 MHz, CDCl₃) δ 8.16 (d, J=1.6 Hz, 1H), 7.91(dd, J=8.2 Hz, 1.6 Hz, 1H), 7.57 (d, J=7.6 Hz, 1H), 7.39 (m, 2H), 7.17(m, 2H).

Compound bo: 5-fluoro-2-(2H-tetrazol-2-yl)benzoic acid

To a 20 mL microwave tube was added 2-bromo-5-fluorobenzoic acid (1.08g, 4.93 mmol, 1.0 eq), Cs₂CO₃ (3 g, 9.86 mmol, 2.0 eq), CuI (0.09 g,0.49 mmol, 0.1 eq) and DMF (10 mL). N, N′-dimethylglycine (0.09 g, 0.99mmol, 0.2 eq) was added and the mixture was irradiated at 120° C. for 1h. The reaction mixture was cooled to RT and acidified to pH5. Themixture was concentrated to provide the crude which was purified bycolumn chromatography on silica gel to obtain the desired product.ESI-MS (m/z): 208.88 [M+1]⁺.

Compound bp: 5-chloro-2-(2H-tetrazol-2-yl)benzoic acid

The acid was prepared following the same general protocol as described5-fluoro-2-(2H-tetrazol-2-yl)benzoic acid using 5-chloro-2-iodobenzoicacid. ¹H NMR (400 MHz, CDCl₃) δ 9.30 (s, 1H), 8.06 (d, J=1.6 Hz, 1H),7.96 (d, J=8.2 Hz, 1.6 Hz, 1H), 7.92 (d, J=8.2 Hz, 1H). ESI-MS (m/z):224.88 [M+1]⁺.

Compound bq: 5-chloro-2-(2-methyl-2H-tetrazol-5-yl)benzoic acid

Step 1: methyl 2-bromo-5-chlorobenzoate

To a mixture of 2-bromo-5-chlorobenzoic acid (10.4 g, 44.16 mmol, 1.0eq) in MeOH (250 mL) at ice bath was added slowly SOCl₂ (4.8 mL, 66.24mmol, 1.5 eq). The reaction mixture was warm to RT and heated at 80° C.oil bath overnight. The completion of the reaction was monitored byanalytical HPLC. When complete, the reaction mixture was cooled to RTand concentrated. The crude was dissolved with EtOAc and washed withSat'd NaHCO₃, brine and dried over Na₂SO₄. The organic layer wasconcentrated to obtain the desired product for the next step with nofurther purification.

Step 2: methyl 5-chloro-2-cyanobenzoate

A mixture of methyl 2-bromo-5-chlorobenzoate (8.275 g, 33.17 mmol, 1.0eq) and ZnCN (2.03 g, 17.25 mmol, 0.52 eq) in DMF (40 mL) was degassed,and then Pd(PPh₃)₄ (0.767 g, 0.66 mmol, 0.02 eq) was added. The mixturewas heated overnight at 90° C. at oil bath. The completion of thereaction was monitored by analytical HPLC. When complete, the reactionmixture was cooled to RT and concentrated to provide the crude which waspurified by column chromatography on silica gel to obtain the desiredproduct.

Step 3: methyl 5-chloro-2-(2H-tetrazol-5-yl)benzoate

A mixture of methyl 5-chloro-2-cyanobenzoate (5.31 g, 26.11 mmol, 1.0eq), NaN₃ (5.1 g, 78.33 mmol, 3.0 eq) and triethylamine hydrochloride(10.8 g, 78.33 mmol, 3.0 eq) in toluene (100 mL) was heated overnight at100° C. oil bath. The completion of the reaction was monitored byanalytical HPLC. When complete, the reaction mixture was cooled to RTand concentrated to provide the crude which was purified by columnchromatography on silica gel to obtain the desired product. ESI-MS(m/z): 238.98 [M+1]⁺.

Step 4: methyl 5-chloro-2-(2-methyl-2H-tetrazol-5-yl)benzoate

To a mixture of methyl 5-chloro-2-(2H-tetrazol-5-yl)benzoate (1.411 g,5.91 mmol, 1.0 eq) and K₂CO₃ (1.23 g, 8.87 mmol, 1.5 eq) in DMF (20 mL)was added MeI (0.55 mL, 8.87 mmol, 1.5 eq). The mixture was stirredovernight at 50° C. oil bath. The completion of the reaction wasmonitored by analytical HPLC. When complete, the reaction mixture wascooled to RT and concentrated to provide the crude, which was dissolvedwith EtOAc, washed with water, sat'd NaHCO₃ and brine. The organic layerwas concentrated to obtain the crude which was purified by columnchromatography on silica gel to obtain the major fraction which is thedesired product. ESI-MS (m/z): 252.92 [M+1]⁺.

Step 5: 5-chloro-2-(2-methyl-2H-tetrazol-5-yl)benzoic acid

The acid was prepared following the same general protocol as describedfor 5-(5-fluoropyridin-2-yl)-2-methylthiazole-4-carboxylic acid inCompound az in Step 2 using methyl5-chloro-2-(2-methyl-2H-tetrazol-5-yl)benzoate. ESI-MS (m/z): 238.90[M+1]⁺.

Compound br: 5-methyl-2-(2-methyl-2H-tetrazol-5-yl)benzoic acid

The acid was prepared following the same general protocol as describedfor 5-chloro-2-(2-methyl-2H-tetrazol-5-yl)benzoic acid in Compound bqusing methyl 2-cyano-5-methylbenzoate. ESI-MS (m/z): 218.90 [M+1]⁺.

Compound bs: 5: 5-methyl-2-(1-methyl-1H-tetrazol-5-yl)benzoic acid

The acid was prepared following the same general protocol as describedfor 5-chloro-2-(2-methyl-2H-tetrazol-5-yl)benzoic acid in Compound bqusing methyl 2-cyano-5-methylbenzoate and was the minor isomer isolatedfrom the reaction. ESI-MS (m/z): 218.9 [M+1]⁺.

Compound bt: 5-chloro-2-(3-methyl-1,2,4-oxadiazol-5-yl)benzoic acid

Step 1: methyl 5-chloro-2-methylbenzoate

The acid was prepared following the same general protocol as described5-chloro-2-(2-methyl-2H-tetrazol-5-yl)benzoic acid in step 1, using5-chloro-2-methylbenzoic acid.

Step 2: methyl 2-(bromomethyl)-5-chlorobenzoate

A solution of compound 2 (6.95 g, 37.63, 1.0 eq mmol),N-bromosuccinimide (7.03 g, 39.51 mmol, 1.05 eq) and benzoyl peroxide(0.55 g, 2.26 mmol, 0.06 eq) in carbon tetrachloride (50 mL) was heatedto reflux for overnight. The completion of the reaction was monitored byanalytical HPLC. When complete, the reaction mixture was cooled to RTand concentrated to provide the crude, which was dissolved with EtOAc,washed with sat'd NaHCO₃, dried over sodium sulfate, concentrated andpurified by flash column chromatography to afford the desired product.

Step 3: methyl 5-chloro-2-formylbenzoate

A mixture of methyl 2-(bromomethyl)-5-chlorobenzoate (9.9 g, 37.63 mmol,1.0 eq) and N-methylmorpholine oxide (10.0 g, 94.08 mmol, 2.5 eq) inDMSO (40 mL) was stirred overnight at RT. The completion of the reactionwas monitored by analytical HPLC. When complete, the mixture was dilutedwith EtOAc, washed with sat'd NaHCO₃, dried over sodium sulfate,concentrated and purified by flash column chromatography to afford thedesired product.

Step 4: 4-chloro-2-(methoxycarbonyl)benzoic acid

methyl 5-chloro-2-formylbenzoate (3.3 g, 16.60 mmol, 1.0 eq) wasdissolved in t-BuOH (160 mL) and water (16 mL). Then 2-methyl-2-butene(8.8 mL, 83.0 mmol, 5 eq) and NaH₂PO₄ (2.0 g, 16.60 mmol, 1.0 eq) wereadded. To the stirred suspension was portionwise added NaClO₂ (3.8 g,33.2 mmol, 2 eq.) at rt. After 1 hr at rt, the mixture was diluted withAcOEt and water, then acidified with aqueous KHSO₄ solution toapproximately pH 4. The organic extract was washed with brine, driedover Na₂SO₄, filtered and concentrated to give crude which was used fornext step without purification.

Step 5: methyl(Z)-2-((((1-aminoethylidene)amino)oxy)carbonyl)-5-chlorobenzoate4-chloro-2-(methoxycarbonyl)benzoate

To a mixture of 4-chloro-2-(methoxycarbonyl)benzoic acid (0.414 g, 1.93mmol, 1.0 eq) and DMF (1 drop) in DCM (10 mL) at 0° C. was added oxalylchloride (0.18 mL, 2.10 mmol, 1.1 eq) dropwise. Gas evolution commencedimmediately and after 5 min the ice bath was removed. When gas evolutionhad ceased and the mixture was stirred at RT for another hour and thenconcentrated. The crude was dissolved in fresh DCM (10 mL) and treatedwith N-hydroxyacetamidine (0.17 g, 2.31 mmol, 1.2 eq) in severalportions followed by TEA (0.8 mL, 5.79 mmol, 3.0 eq). The mixture wasstirred overnight at RT and then concentrated in vacuo to obtain thecrude, which was purified by flash column chromatography to affordmixture of (Z)-isomer and (E)-isomer. ESI-MS (m/z): 270.92 [M+1]⁺.

Step 6: methyl 5-chloro-2-(3-methyl-1,2,4-oxadiazol-5-yl)benzoate

The mixture (obtained from the above step) in Toluene (10 mL) wasrefluxed overnight. The completion of the reaction was monitored byanalytical HPLC. When complete, the mixture was diluted with EtOAc,washed with sat'd NaHCO₃, dried over sodium sulfate, concentrated andpurified by flash column chromatography to afford the desired product.ESI-MS (m/z): 252.94 [M+1]⁺.

Step 7: 5-chloro-2-(3-methyl-1,2,4-oxadiazol-5-yl)benzoic acid

The acid was prepared following the same general protocol as describedfor 5-(5-fluoropyridin-2-yl)-2-methylthiazole-4-carboxylic acid Compoundaz in Step 2 using methyl5-chloro-2-(3-methyl-1,2,4-oxadiazol-5-yl)benzoate. ESI-MS (m/z): 238.94[M+1]⁺.

Compound bu: 1-ethyl-4-(pyrimidin-2-yl)-1H-pyrazole-3-carboxylic acid

Step 1: methyl 4-bromo-1-ethyl-1H-pyrazole-3-carboxylate

A solution of methyl 4-bromo-1H-pyrazole-3-carboxylate (1 eq), EtI (1.4eq) and triethylamine (3 eq) in dichloromethane (10 mL) was stirred atroom temperature overnight. After removal of solvent under reducedpressure, the residue was dissolved in ethyl acetate (10 mL) and washedwith 1 M HCl (5 mL), brine (5 mL), dried over Na₂SO₄. Removal of solventunder reduced pressure afforded the title compound as a colorless oil.ESI-MS (m/z): 232.62 [M+H]⁺

Step 2: methyl1-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-3-carboxylate

A mixture of methyl 4-bromo-1-ethyl-1H-pyrazole-3-carboxylate (1 eq),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (1 eq), KOAc(2 eq) and Pd(dppf)Cl₂ (5 mol %) in 1,4-dioxane (10 mL) was stirred at100° C. overnight. The precipitate was removed by filtration and thefiltrate was used for next step without further purification. ESI-MS(m/z): 281.64 [M+H]⁺

Step 3: 1-ethyl-4-(pyrimidin-2-yl)-1H-pyrazole-3-carboxylic acid

To the solution of methyl1-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-3-carboxylatefrom the last step were added 2-bromopyrimidine (1.1 eq), Na₂CO₃ (2 eq),Pd(PPh₃)₄ (10 mol %), 1,4-dioxane (20 mL) and H₂O (5 mL). The mixturewas stirred at 100° C. overnight. After removal of solvents underreduced pressure, the residue was purified by prep-HPLC to afford thetitle compound as a colorless solid. ESI-MS (m/z): 219.18 [M+H]⁺

Compound bv: 1-isopropyl-4-(pyrimidin-2-yl)-1H-pyrazole-3-carboxylicacid

The title compound was synthesized as a colorless solid following thesame general protocol as described for1-ethyl-4-(pyrimidin-2-yl)-1H-pyrazole-3-carboxylic acid using methyl4-bromo-1H-pyrazole-3-carboxylate and 2-iodopropane. ESI-MS (m/z):232.81 [M+H]⁺

Compound bw:4-(pyrimidin-2-yl)-1-(2,2,2-trifluoroethyl)-1H-pyrazole-3-carboxylicacid

The title compound was synthesized as a colorless solid following thesame general protocol as described for1-ethyl-4-(pyrimidin-2-yl)-1H-pyrazole-3-carboxylic acid using methyl4-bromo-1H-pyrazole-3-carboxylate and 2,2,2-trifluoroethyltrifluoromethanesulfonate. ESI-MS (m/z): 272.88 [M+H]⁺

Compound bx: 5-fluoro-2-(2-methyl-2H-tetrazol-5-yl)benzoic acid

The acid was prepared following the same general protocol as describedfor 5-chloro-2-(2-methyl-2H-tetrazol-5-yl)benzoic acid in Compound bqusing methyl 2-cyano-5-fluorobenzoate. ESI-MS (m/z): 222.90 [M+1]⁺.

Compound by: 4-(5-chloropyridin-2-yl)-1-methyl-1H-pyrazole-3-carboxylicacid

The title compound was made following the same general protocol asdescribed for Compound af using methyl4-bromo-1-methyl-1H-pyrazole-3-carboxylate and5-chloro-2-(tributylstannyl)pyridine. ESI-MS (m/z): 237.78 [M+1]⁺.

Compound bz: 4-(4-chloropyridin-2-yl)-1-methyl-1H-pyrazole-3-carboxylicacid

The title compound was made following the same general protocol asdescribed for Compound af using methyl4-bromo-1-methyl-1H-pyrazole-3-carboxylate and4-chloro-2-(tributylstannyl)pyridine. ESI-MS (m/z): 237.78 [M+1]⁺.

Compound ca: 4-(5-methoxypyridin-2-yl)-1-methyl-1H-pyrazole-3-carboxylicacid

The title compound was made following the same general protocol asdescribed for Compound af using methyl4-bromo-1-methyl-1H-pyrazole-3-carboxylate and4-methoxy-2-(tributylstannyl)pyridine. ESI-MS (m/z): 233.94 [M+1]⁺.

Compound cb: 1-methyl-4-phenyl-1H-pyrazole-3-carboxylic acid

The title compound was made following the same general protocol asdescribed for Compound ao using methyl4-bromo-1-methyl-1H-pyrazole-3-carboxylate and phenylboronic acid.ESI-MS (m/z): 202.86 [M+1]⁺.

Compound cc: 4-(4-fluorophenyl)-1-methyl-1H-pyrazole-3-carboxylic acid

The title compound was made following the same general protocol asdescribed for Compound ao using methyl4-bromo-1-methyl-1H-pyrazole-3-carboxylate and (4-fluorophenyl)boronicacid ESI-MS (m/z): 220.84 [M+1]⁺.

Compound cd: 4-(3-chlorophenyl)-1-methyl-1H-pyrazole-3-carboxylic acid

The title compound was made following the same general protocol asdescribed for Compound ao using methyl4-bromo-1-methyl-1H-pyrazole-3-carboxylate and (3-chlorophenyl)boronicacid ESI-MS (m/z): 236.86 [M+1]⁺.

Compound ce: 5-(4-fluorophenyl)-2-methyloxazole-4-carboxylic acid

The title compound was made following the same general protocol asdescribed for Compound ao using ethyl5-bromo-2-methyloxazole-4-carboxylate and (4-fluorophenyl)boronic acid.ESI-MS (m/z): 221.86 [M+1]⁺.

Compound cf: 2-methyl-5-phenyloxazole-4-carboxylic acid

The title compound was made following the same general protocol asdescribed for Compound ao using ethyl5-bromo-2-methyloxazole-4-carboxylate and phenylboronic acid. ESI-MS(m/z): 203.87 [M+1]⁺.

Compound cg: 2-methyl-5-(pyridin-3-yl)oxazole-4-carboxylic acid

The title compound was made following the same general protocol asdescribed for Compound ao using ethyl5-bromo-2-methyloxazole-4-carboxylate and 3-pyridylboronic acid. ESI-MS(m/z): 204.93 [M+1]⁺.

Compound ch: 2-methyl-5-(pyridin-2-yl)-2H-1,2,3-triazole-4-carboxylicacid

The acid was prepared following the same general protocol as describedfor 5-(5-fluoropyridin-2-yl)-2-methylthiazole-4-carboxylic acid inCompound az using 2-(tributylstannyl)pyridine and methyl5-bromo-2-methyl-2H-1,2,3-triazole-4-carboxylate in Step 2. ESI-MS(m/z): 204.97 [M+1]⁺.

Compound ci: 2-methyl-5-phenyl-2H-1,2,3-triazole-4-carboxylic acid

The title compound was made following the same general protocol asdescribed for Compound ao using methyl5-bromo-2-methyl-2H-1,2,3-triazole-4-carboxylate and phenylboronic acid.ESI-MS (m/z): 203.20 [M+1]⁺.

Compound cj: 5-(4-fluorophenyl)-2-methyl-2H-1,2,3-triazole-4-carboxylicacid

The title compound was made following the same general protocol asdescribed for Compound ao using methyl5-bromo-2-methyl-2H-1,2,3-triazole-4-carboxylate and(4-fluorophenyl)boronic acid ESI-MS (m/z): 221.19 [M+1]⁺.

Compound ck:5-(5-chloropyridin-2-yl)-2-methyl-2H-1,2,3-triazole-4-carboxylic acid

The acid was prepared following the same general protocol as describedfor 4-(5-fluoropyrimidin-2-yl)-1-methyl-1H-pyrazole-3-carboxylic acid inCompound aa using 5-bromo-2-methyl-2H-1,2,3-triazole-4-carboxylic acid.ESI-MS (m/z): 238.81 [M+1]⁺.

Compound cl: 6-methoxy-3-(2H-1,2,3-triazol-2-yl)picolinic acid

Step 1: 5-bromo-2-methoxypyridine 1-oxide

To a solution of 5-bromo-2-methoxypyridine (1 eq) in CHCl₃ was addedMCPBA (4 eq). The reaction was warmed to 100° C. for 2 h, and thencooled to room temperature. The reaction was cooled to 0° C. andquenched with aqueous Na₂S₂O₃ solution and saturated aqueous NaHCO₃. Thelayers were separated, and the organic layer was washed with sat. aq.NaHCO₃, brine, dried (MgSO₄) and concentrated to give the title compoundwhich was used without further purification.

Step 2: 3-bromo-6-methoxypicolinonitrile

To a solution of 5-bromo-2-methoxypyridine 1-oxide (1 eq) in CH₃CN wasadded TEA (3 eq) followed by TMSCN (4 eq). The reaction was warmed to100° C. for 14 h, and then cooled and quenched with saturated aqueousNaHCO₃ and diluted with EtOAc. The layers were separated, and theorganic layer was washed with sat. aq. NaHCO₃, brine, dried (MgSO₄) andconcentrated in vacuo to give the title compound which was purified bychromatography on SiO₂ (EtOAc/hex) to give the title compound. ESI-MS(m/z): 213.19 [M+1]+.

Step 3: 3-bromo-6-methoxypicolinic acid

To a solution of 3-bromo-6-methoxypicolinonitrile (1 eq) in EtOH wasadded NaOH (3 eq). The reaction was warmed to 100° C. for 12 h, and thencooled and acidified with 2M HCl until the pH˜4-5. The reaction wasconcentrated to remove the EtOH, and then diluted with EtOAc and water.The layers were separated. The organic layer was washed with brine,dried (MgSO₄) and concentrated in vacuo to give the title compound whichwas used without further purification. ESI-MS (m/z): 231.99 [M+1]+.

Step 4: 6-methoxy-3-(2H-1,2,3-triazol-2-yl)picolinic acid

A mixture of 3-bromo-6-methoxypicolinic acid (1 eq), 1,2,3-triazole (2eq), (1S,2S)—N1,N2-dimethylcyclohexane-1,2-diamine (0.2 eq), Cs₂CO₃ (2eq) and CuI (0.5 mol %) in dioxane/H₂O (200/1) was degassed and heatedat 100° C. for 4 h. The reaction was cooled to RT, diluted with MeOH,and acidified with AcOH to pH˜4-5. The solvent was removed in vacuo toobtain the crude which was purified by silica gel chromatography (0-100%DCM/EtOAc) to obtain the title compound. ESI-MS (m/z): 221.1, [M+1]⁺.

Compound cm: 3-(2H-1,2,3-triazol-2-yl)-6-(trifluoromethyl)picolinic acid

The title compound was made following the same general protocol asdescribed for Compound cl starting with5-bromo-2-(trifluoromethyl)pyridine. ESI-MS (m/z): 259.1 [M+1]⁺.

Compound cn: 6-methyl-3-(2-methyl-2H-tetrazol-5-yl)picolinic acid

The acid was prepared following the same general protocol as describedfor 5-chloro-2-(2-methyl-2H-tetrazol-5-yl)benzoic acid in Compound bqusing methyl 3-cyano-6-methylpicolinate. ESI-MS (m/z): 220.23 [M+1]+.

Compound co:1-methyl-4-(6-(trifluoromethyl)pyridin-2-yl)-1H-pyrazole-3-carboxylicacid

The title compound was synthesized following the same general protocolas described for4-(5-chloropyrimidin-2-yl)-1-methyl-1H-pyrazole-3-carboxylic acid using(3-(methoxycarbonyl)-1-methyl-1H-pyrazol-4-yl)boronic acid and2-bromo-6-(trifluoromethyl)pyridine. ESI-MS (m/z): 272.05 [M+1]⁺.

Compound cp: 1-methyl-4-(pyrimidin-5-yl)-1H-pyrazole-3-carboxylic acid

The title compound was synthesized following the same general protocolas described for4-(5-chloropyrimidin-2-yl)-1-methyl-1H-pyrazole-3-carboxylic acid using(3-(methoxycarbonyl)-1-methyl-1H-pyrazol-4-yl)boronic acid and5-bromopyrimidine. ESI-MS (m/z): 205.03 [M+1]+.

Compound cq: 1-methyl-4-(pyrazin-2-yl)-1H-pyrazole-3-carboxylic acid

The title compound was synthesized following the same general protocolas described for4-(5-chloropyrimidin-2-yl)-1-methyl-1H-pyrazole-3-carboxylic acid using(3-(methoxycarbonyl)-1-methyl-1H-pyrazol-4-yl)boronic acid and2-bromopyrazine. ESI-MS (m/z): 205.11 [M+1]+.

Compound cr: 1-methyl-4-(pyrimidin-4-yl)-1H-pyrazole-3-carboxylic acid

Step 1:1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-3-carboxylicacid

A mixture of methyl 4-bromo-1-methyl-1H-pyrazole-3-carboxylic acid (1eq), 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (1 eq),KOAc (2 eq) and Pd(dppf)Cl₂ (5 mol %) in 1,4-dioxane (10 mL) was stirredat 100° C. overnight. The precipitate was removed by filtration and thefiltrate was used for next step without further purification. ESI-MS(m/z): 267.20 [M+1]⁺.

Step 2: 1-methyl-4-(pyrimidin-4-yl)-1H-pyrazole-3-carboxylic acid

To the solution of crude1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-3-carboxylicacid from Step 1 were added 4-chloropyrimidine (1.1 eq), Na₂CO₃ (2 eq),Pd(PPh₃)₄ (10 mol %), 1,4-dioxane (20 mL) and H₂O (5 mL). The mixturewas stirred at 100° C. overnight. After removal of solvents underreduced pressure, the residue was purified by prep-HPLC to afford thetitle compound as a colorless solid. ESI-MS (m/z): 205.17 [M+1]+.

Compound cs: 5,6′-dimethyl-[2,3′-bipyridine]-2′-carboxylic acid

Step 1: 5,6′-dimethyl-[2,3′-bipyridine]-2′-carbonitrile

To a mixture of 3-bromo-6-methylpicolinonitrile (1.0 eq),(5-methylpyridin-2-yl)boronic acid (1.3 eq) and K₂CO₃ (3.0 eq) indioxane/H₂O (4:1) was added Pd(PPh₃)₄ (10 mol %). The mixture wasdegassed and then heated for 30 min at 120° C. in a microwave reactor.The completion of the reaction was monitored by analytical HPLC. Whencomplete, the reaction mixture was cooled to RT and diluted with EtOAcand washed with H₂O and the layers were separated. The aqueous layer wasextracted with EtOAc (2×). The combined organic layers were concentratedto provide the crude which was purified by column chromatography onsilica gel to obtain the desired product. ESI-MS (m/z): 210.09 [M+1]⁺.

Step 2: 5,6′-dimethyl-[2,3′-bipyridine]-2′-carboxylic acid

A mixture of 5,6′-dimethyl-[2,3′-bipyridine]-2′-carbonitrile (1.0 eq)and NaOH (5 eq) in MeOH/H₂O (1/1) was warmed to reflux overnight. After12 h, the reaction was concentrated to remove the MeOH. EtOAc was added,and 2M HCl was added until pH˜6. The layers were separated. The aqueouslayer was extracted with EtOAc (2×). The combined organics were washedwith brine, dried (MgSO₄) and concentrated to afford the title acid as anear colorless solid which was used without further purification. ESI-MS(m/z): 229.26 [M+1]⁺.

Compound ct:4-(5-fluoropyrimidin-2-yl)-1,5-dimethyl-1H-pyrazole-3-carboxylic acid

The title compound was prepared following the same general procedure asdescribed for Compound aa using tert-butyl4-bromo-1,5-dimethyl-1H-pyrazole-3-carboxylate and2-chloro-5-(trifluoromethyl)pyrimidine. ESI-MS (m/z): 236.80 [M+1]⁺.

Compound cu: 6-methyl-3-(1-methyl-1H-pyrazol-4-yl)picolinic acid

Step 1: methyl 6-methyl-3-(1-methyl-1H-pyrazol-4-yl)picolinate

To a solution of methyl 3-bromo-6-methylpicolinate (1 eq) and(1-methyl-1H-pyrazol-4-yl)boronic acid (1.5 eq) in DMF/H₂O (5:1) wasadded K₂CO₃ (1.5 eq) and Pd(PPh₃)₄ (2.5 mol %). The mixture was degassedand then heated overnight in an 80° C. oil bath under argon. When thereaction was complete as judged by analytical HPLC, the reaction mixturewas cooled to RT, and filtered through a celite pad to remove K₂CO₃ andPd. The filter cake was washed with toluene. The filtrate was dilutedwith toluene was washed with H₂O and the layers were separated. Theaqueous layer was extracted with toluene (2×). The combined organiclayers were dried (Na₂SO₄) and concentrated to provide the titlecompound which was purified by chromatography on SiO2 (EtOAc/hex).ESI-MS (m/z): 213.95 [M+1]⁺.

Step 2: 6-methyl-3-(1-methyl-1H-pyrazol-4-yl)picolinic acid

Methyl 6-methyl-3-(1-methyl-1H-pyrazol-4-yl)picolinate was stirred inTHF/1M LiOH (1/1 v:v) until starting material was consumed as judged byanalytical HPLC. When complete, the reaction was diluted with EtOAc, and1M HCl was added to adjust the pH˜5-6. The layers were separated, andthe aqueous layer was extracted with EtOAc (2×). The combined organiclayers were washed with brine, dried (MgSO₄) and concentrated to affordthe title compound as a solid that was used without furtherpurification. ESI-MS (m/z): 217.97[M+1]⁺.

Compound cv: 6-chloro-1,2-dimethyl-1H-benzo[d]imidazole-4-carboxylicacid

To a solution of methyl 2,3-diamino-5-chlorobenzoate (1 eq) and1,1,1-trimethoxyethane (5 eq) in MeOH was added NH₂SO₃H. The reactionwas stirred at room temperature for 12 h, and then concentrated invacuo. The crude was taken up in EtOAc, and washed with sat. aq. NaHCO₃,brine, dried (MgSO₄) and concentrated in vacuo. Purification bychromatography on SiO₂ (EtOAc/hex afforded the benzimidazole.

To a solution of the benzimidazole in THF was added NaH (1.4 eq). After30 min, MeI (2 eq) was added. When the starting material was consumed asjudged by analytical HPLC, the reaction was quenched with 0.5 M HCl, anddiluted with EtOAc. The layers were separated, and the organic layer waswashed with brine, dried (MgSO₄) and concentrated in vacuo. The crudeN-methyl benzimidazole was purified by chromatography on SiO₂(EtOAc/hex).

To a solution of the crude N-methyl benzimidazole in MeOH/H₂O was added1M KOH. The reaction was warmed to 50° C. until starting material wasconsumed as judged by T.L.C. analysis. The reaction was cooled to roomtemperature, acidified with 2 M HCl until the pH was ˜5-6, andconcentrated in vacuo. The crude was taken up in EtOAc and water, andthe layers were separated. The organic layer was washed with brine,dried (MgSO₄) and concentrated to give the title compound as a lightyellow solid. ESI-MS (m/z): 225.1 [M+1]⁺.

Synthesis of Compounds 1 and 2 Compound 1:((2S,3R)-5,5-difluoro-3-methyl-2-(((5-(trifluoromethyl)pyrimidin-2-yl)amino)methyl)piperidin-1-yl)(5-fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone

Step 1: (2S,3R)-benzyl5,5-difluoro-3-methyl-2-(((5-(trifluoromethyl)pyrimidin-2-yl)amino)methyl)piperidine-1-carboxylate

To a mixture of (2S,3R)-Benzyl2-(aminomethyl)-5,5-difluoro-3-methylpiperidine-1-carboxylate (1 eq) andK₂CO₃ (2 eq) in DMF (20 mL) was added2-chloro-5-(trifluoromethyl)pyrimidine (2 eq). The reaction was warmedto 80° C. for 2 h wherein the starting material was judged consumed asindicated by reverse-phase analytical HPLC. The reaction was cooled, anddiluted with EtOAc, and water. The layers were separated, and theorganic phase was washed with water (3×), brine, dried (MgSO₄) andconcentrated. The crude residue was purified by chromatography on SiO₂(EtOAc/hex) to give the title compound as a near colorless oil whichsolidified. ESI-MS (m/z): 445.4 [M+1]⁺.

Step 2:N-(((2S,3R)-5,5-difluoro-3-methylpiperidin-2-yl)methyl)-5-(trifluoromethyl)pyrimidin-2-aminehydrobromide

To the carbamate from the previous step was added to 30% HBr in HOAc.The reaction was stirred at rt (1-2 h) until sm was consumed as judgedby HPLC analysis. The reaction was concentrated in vacuo to give thetitle compound as a pale yellow foam which was used without furtherpurification. ESI-MS (m/z): 311.3 [M+1]⁺.

Step 3:((2S,3R)-5,5-difluoro-3-methyl-2-(((5-(trifluoromethyl)pyrimidin-2-yl)amino)methyl)piperidin-1-yl)(5-fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone

To a solution ofN-(((2S,3R)-5,5-difluoro-3-methylpiperidin-2-yl)methyl)-5-(trifluoromethyl)pyrimidin-2-aminehydrobromide (10 mg) in DMF (0.5 mL) was added DIEA (3 eq) followed by5-fluoro-2-(2H-1,2,3-triazol-2-yl)benzoic acid (6 mg) and HATU (8 mg).The reaction was allowed to stir at room temperature for 15 h, and wasthen diluted with EtOAc and washed with 1 M HCl, sat aq. NaHCO₃, brine,dried (MgSO₄), and concentrated. The crude residue was purified bychromatography on silica gel (EtOAc/hex) to give the title compound as acolorless oil which solidified. ESI-MS (m/z): 500.09 [M+1]⁺.

Compound 2:((2S,3R)-2-(((5-chloropyrimidin-2-yl)amino)methyl)-5,5-difluoro-3-methylpiperidin-1-yl)(5-fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone

Step 1: (2S,3R)-benzyl2-(((5-chloropyrimidin-2-yl)amino)methyl)-5,5-difluoro-3-methylpiperidine-1-carboxylate

The title compound was prepared following the same general procedure asdescribed in Compound 1 using 2,5-dichloropyrimidine in Step 1. ESI-MS(m/z): 411.2 [M+1]⁺.

Step 2:5-chloro-N-(((2S,3R)-5,5-difluoro-3-methylpiperidin-2-yl)methyl)pyrimidin-2-amine

The title compound was prepared following the same general protocol asdescribed in Compound 1, Step 2. ESI-MS (m/z): 277.1 [M+1]⁺.

Step 3:((2S,3R)-2-(((5-chloropyrimidin-2-yl)amino)methyl)-5,5-difluoro-3-methylpiperidin-1-yl)(5-fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone

The title compound was prepared following the same general procedure asdescribed in Compound 1, Step 3, using5-fluoro-2-(2H-1,2,3-triazol-2-yl)benzoic acid. ESI-MS (m/z): 466.19[M+1]⁺.

Compounds 3-15, 19-53, 58-98, 100-101, 103-119, 121-161, 163-203,210-211, 217-219, 221, 224-227, 229-233, 237-242, 249-250, 252-253, and254 were prepared in a manner analogous to that shown above for Compound1.

Compound 68:((2S,3R)-5,5-difluoro-3-methyl-2-(((5-(trifluoromethyl)pyrimidin-2-yl)amino)methyl)piperidin-1-yl)(5-(4-fluorophenyl)-2-methylthiazol-4-yl)methanone

¹H NMR (MeOD, 400 MHz) δ 8.42 (s, 2H), 7.44-7.39 (m, 2H), 7.18-7.13 (m,2H), 4.9-4.77 (m, 1H), 4.20 (br s, 1H), 3.82-3.60 (m, 1H), 3.47 (m, 2H),3.4-3.25 (m, 1H), 2.45 (s, 3H), 2.0-1.75 (m, 2H), 1.35-1.1 (m, 2H), 0.87(d, 3H); ESI-MS (m/z): 530.12 [M+1]⁺.

Compound 97:((2S,3R)-5,5-difluoro-3-methyl-2-(((5-(trifluoromethyl)pyrimidin-2-yl)amino)methyl)piperidin-1-yl)(1-methyl-4-(pyrimidin-2-yl)-1H-pyrazol-3-yl)methanone

¹H NMR (CDCl₃, 400 MHz) δ 8.80-8.79 (m, 2H), 8.54 (s, 0.6H), 8.45-8.42(m, 1.4H), 8.20 (s, 0.6H), 8.10 (s, 0.4H), 7.25-7.20 (m, 0.4H),7.13-7.09 (m, 1H), 7.02-7.0 (m, 0.6H), 5.29-5.26 (m, 0.6H), 5.20-5.05(t, 0.4H), 4.25-4.16 (m, 0.6H), 4.10-4.05 (m, 0.4H), 3.99 (s, 1.9H),3.97 (s, 1.1H), 3.9-3.7 (m, 1H), 3.55-3.45 (m, 1H), 3.40-3.25 (m, 0.6H),3.10-3.0 (m, 0.4H), 2.6-2.45 (m, 1H), 2.4-2.1 (m, 1H), 2.05-1.75 (m,1H), 1.20 (d, 1.9H), 0.99 (d, 1.1H); ESI-MS (m/z): 497.38 [M+1]⁺.

Compound 98:((2S,3R)-2-(((5-chloropyrimidin-2-yl)amino)methyl)-5,5-difluoro-3-methylpiperidin-1-yl)(1-methyl-4-(pyrimidin-2-yl)-1H-pyrazol-3-yl)methanone

¹H NMR (DMSO-d₆, 400 MHz) δ 8.79-8.78 (d, 0.6H), 8.63-8.62 (d, 1.4H),8.48 (s, 0.3H), 8.4-8.3 (br s, 0.5H), 8.26 (s, 0.7H), 8.2-8.1 (m, 1.5H),7.32-7.28 (m, 1H), 7.23-7.21 (m, 0.7H), 7.05-7.0 (m, 0.3H), 5.0-4.95 (m,0.3H), 4.85-4.75 (m, 0.7H), 4.0-3.95 (m, 0.7H), 3.91 (s, 1H), 3.85-3.8(m, 0.3H), 3.67 (s, 2H), 3.7-3.3 (m, 3H), 2.10-1.95 (m, 3H), 1.10 (d,1H), 0.80 (d, 2H); ESI-MS (m/z): 463.2 [M+1]⁺.

Compound 159:((2S,3R)-5,5-difluoro-3-methyl-2-(((5-(trifluoromethyl)pyrazin-2-yl)amino)methyl)piperidin-1-yl)(1-methyl-4-(pyrimidin-2-yl)-1H-pyrazol-3-yl)methanone

¹H NMR (DMSO-d₆, 400 MHz) δ 8.71-8.69 (d, 0.4H), 8.62-8.60 (d, 1.6H),8.43 (s, 0.4H), 8.18 (s, 1.6H), 7.95 (br s, 1H), 7.88 (s, 1H), 7.27-7.21(m, 1H), 5.0-4.79 (m, 1H), 3.85 (s, 0.5H), 4.0-3.75 (m, 1H), 3.55 (s,2.5H), 3.6-3.50 (m, 2H), 3.40-3.30 (m, 1H), 2.15-1.95 (m, 3H), 1.11 (d,0.5H), 0.82 (d, 2.5H); ESI-MS (m/z): 497.24 [M+1]⁺.

Compound 200:((2S,3R)-5,5-difluoro-3-methyl-2-(((5-(trifluoromethyl)pyridin-2-yl)amino)methyl)piperidin-1-yl)(1-methyl-4-(pyrimidin-2-yl)-1H-pyrazol-3-yl)methanone

¹H NMR (DMSO-d₆, 400 MHz) δ 8.73 (d, 0.6H), 8.64 (d, 1.4H), 8.5 (s,0.3H), 8.45 (br s, 0.3H), 8.20 (s, 0.7H), 8.15 (s, 0.7H), 7.7-7.6 (m,0.3H), 7.55-7.5 (m, 0.7H), 7.30-7.25 (m, 0.3H), 7.25-7.15 (m, 1.7H),6.60-6.50 (m, 0.3H), 6.45-6.35 (m, 0.7H), 5.0-4.9 (br s, 0.2H),4.85-4.75 (m, 0.7H), 3.90 (s, 0.7H), 3.95-3.9 (m, 0.5H), 3.59 (s, 2.3H),3.65-3.45 (m, 2.5H), 3.40-3.30 (m, 1H), 2.20-1.95 (m, 3H), 1.15 (d,0.7H), 0.83 (d, 2.3H); ESI-MS (m/z): 496.15 [M+1]⁺.

Compound 202:((2S,3R)-5,5-difluoro-3-methyl-2-(((5-(trifluoromethyl)pyridin-2-yl)amino)methyl)piperidin-1-yl)(6-methoxy-3-(2H-1,2,3-triazol-2-yl)pyridin-2-yl)methanone

¹H NMR (CDCl₃, 400 MHz) δ 8.38-8.14 (m, 2H), 7.89 (s, 1H), 7.74 (s, 1H),7.6-7.55 (m, 0.5H), 7.55-7.45 (m, 0.5H), 6.95-6.92 (m, 1H), 6.6-6.35 (m,2H), 5.2-5.05 (m, 0.5H), 5.0-4.9 (m, 0.5H), 4.25-4.15 (m, 0.5H), 3.98(s, 1.6H), 3.92 (s, 1.4H), 3.9-3.6 (m, 2.5H), 3.5-3.35 (m, 0.5H),3.1-2.95 (m, 0.5H), 2.8-2.7 (m, 0.5H), 2.5-2.4 (m, 0.5H), 2.3-2.0 (m,2H), 1.4 (d, 1.6H), 1.08 (d, 1.4H); ESI-MS (m/z): 512.5 [M+1]⁺.

Compound 203:(3-(2H-1,2,3-triazol-2-yl)-6-(trifluoromethyl)pyridin-2-yl)((2S,3R)-5,5-difluoro-3-methyl-2-(((5-(trifluoromethyl)pyridin-2-yl)amino)methyl)piperidin-1-yl)methanone

¹H NMR (CDCl₃, 400 MHz) δ 8.66-8.60 (m, 1H), 8.37-8.33 (m, 1H),7.95-7.84 (m, 3H), 7.58-7.54 (m, 1H), 6.6-6.4 (m, 2H), 5.2-5.1 (m,0.2H), 4.99-4.92 (t, 0.8H), 4.20-4.00 (m, 1.5H), 4.0-3.7 (m, 0.5H),3.5-3.3 (m, 1H), 3.15-3.0 (dd, 1H), 2.70 (br s, 0.8H), 2.5 (br s, 0.2H),2.3-2.2 (m, 1H), 2.1-1.95 (m, 1H), 1.2 (d, 0.6H), 1.02 (d, 2.4H); ESI-MS(m/z): 550.2 [M+1]⁺.

Compound 217:((2S,3R)-5,5-difluoro-3-methyl-2-(((5-(trifluoromethyl)pyrimidin-2-yl)amino)methyl)piperidin-1-yl)(4-(5-fluoropyrimidin-2-yl)-1-methyl-1H-pyrazol-3-yl)methanone

¹H NMR (CDCl₃, 400 MHz) δ 8.8 (s, 1.2H), 8.7 (s, 0.8H), 8.6-8.45 (m,2H), 8.15 (s, 0.6H), 8.0 (s, 0.4H), 7.1 (br s, 0.6H), 6.8 (m, 0.4H),5.35-5.25 (m, 0.6H), 5.2-5.1 (m, 0.4H), 4.2-4.1 (m, 1H), 3.98 (s, 1.6H),3.97 (s, 1.4H), 3.9-3.75 (m, 1H), 3.6-3.55 (m, 0.6H), 3.5-3.4 (m, 0.4H),3.35-3.2 (m, 0.6H), 3.2-3.0 (m, 0.4H), 2.6-2.35 (m, 1H), 2.3-2.1 (m,1H), 2-1.8 (m, 1H), 1.2 (d, 1.8H), 1.0 (d, 1.2H); ESI-MS (m/z): 515.3[M+1]⁺.

Compound 218:(4-(5-chloropyrimidin-2-yl)-1-methyl-1H-pyrazol-3-yl)((2S,3R)-5,5-difluoro-3-methyl-2-(((5-(trifluoromethyl)pyrimidin-2-yl)amino)methyl)piperidin-1-yl)methanone

¹H NMR (CDCl₃, 400 MHz) δ 8.85 (s, 1.2H), 8.75 (s, 0.8H), 8.6-8.4 (m,2H), 8.2 (s, 0.6H), 8.05 (s, 0.4H), 7.0 (br s, 0.6H), 6.68 (m, 0.4H),5.35-5.25 (m, 0.6H), 5.2-5.1 (m, 0.4H), 4.15-4.05 (m, 1H), 4.07 (s,1.6H), 4.06 (s, 1.4H), 3.9-3.75 (m, 1H), 3.6-3.5 (m, 0.6H), 3.5-3.4 (m,0.4H), 3.35-3.2 (m, 0.6H), 3.2-3.0 (m, 0.4H), 2.6-2.4 (m, 1H), 2.3-2.15(m, 1H), 2.05-1.8 (m, 1H), 1.2 (d, 1.8H), 1.0 (d, 1.2H); ESI-MS (m/z):531.3 [M+1]⁺.

Compound 219:((2S,3R)-5,5-difluoro-3-methyl-2-(((5-(trifluoromethyl)pyrimidin-2-yl)amino)methyl)piperidin-1-yl)(1-methyl-4-(5-methylpyrimidin-2-yl)-1H-pyrazol-3-yl)methanone

¹H NMR (DMSO-d₆, 400 MHz) δ 8.75-8.65 (m, 0.5H), 8.65-8.6 (m, 1.0H),8.55-8.5 (m, 0.5H), 8.5-8.4 (m, 1.5H), 8.25-8.15 (m, 0.5H), 7.95-7.85(m, 0.5H), 7.75-7.2 (m, 0.5H), 6.95-6.65 (m, 0.5H), 5.35-5.3 (m, 0.5H),4.85-4.75 (m, 0.5H), 4.5-4.45 (m, 0.5H), 4.05-3.90 (m, 1.0H), 3.89 (s,1.0H), 3.8-3.65 (m, 1.0H), 3.61 (s, 2.0H), 2.25 (s, 1.0H), 2.23 (2.0H),2.05-1.9 (m, 3.0H), 1.5-1.4 (m, 1.0H) 1.11 (d, 1.0H), 0.86 (d, 2.0H)ppm; ESI-MS (m/z): 511.3 [M+1]⁺.

Compound 221:(4-(5-chloropyridin-2-yl)-1-methyl-1H-pyrazol-3-yl)((2S,3R)-5,5-difluoro-3-methyl-2-(((5-(trifluoromethyl)pyrimidin-2-yl)amino)methyl)piperidin-1-yl)methanone

¹H NMR (d₆-DMSO, 400 MHz) δ 8.7-8.5 (m, 1H), 8.4 (m, 1.3H), 8.35 (s,0.3H), 8.3 (m, 0.7H), 8.2 (s, 0.7H), 8.0 (m, 0.7H), 7.9 (dd, 0.3H), 7.8(m, 0.3H), 7.8 (dd, 0.7H), 7.5 (d, 0.3H), 7.35 (d, 0.7H), 5.1 (m, 0.3H),4.8 (m, 0.7H), 3.9 (s, 0.8H), 3.7 (s, 2.2H), 3.6-3.3 (m, 3H), 2.2-1.9(m, 3H), 1.1 (d, 0.6H), 0.9 (d, 2.4H); ESI-MS (m/z): 529.9 [M+1]⁺.

Compound 224:((2S,3R)-5,5-difluoro-3-methyl-2-(((5-(trifluoromethyl)pyrimidin-2-yl)amino)methyl)piperidin-1-yl)(1-methyl-4-(pyrazin-2-yl)-1H-pyrazol-3-yl)methanone

¹H NMR (CDCl₃, 400 MHz) δ 8.8 (d, 1H), 8.55 (d, 1H), 8.5-8.3 (m, 3H),7.8 (d, 1H), 7.3 (m, 0.6H), 6.35 (m, 0.4H), 5.3-5.0 (m, 3H), 4.3 (m,0.5H), 4.0 (s, 1.5H), 3.9 (s, 1.5H), 3.9-2.7 (m, 0.5H), 3.5-3.3 (m,0.5H), 3.1-3.0 (m, 0.5H), 2.4-2.3 (m, 1H), 2.2-1.9 (m, 2H), 1.2 (d,1.5H), 1.0 (d, 1.5H); ESI-MS (m/z): 497.32 [M+1]⁺.

Compound 225:((2S,3R)-5,5-difluoro-3-methyl-2-(((5-(trifluoromethyl)pyrimidin-2-yl)amino)methyl)piperidin-1-yl)(1-methyl-4-(4-methylpyrimidin-2-yl)-1H-pyrazol-3-yl)methanone

¹H NMR (CDCl₃, 400 MHz) δ 8.7 (d, 1.2H), 8.65 (d, 0.8H), 8.6-8.4 (m,2H), 8.2 (s, 0.6H), 8.1 (s, 0.4H), 7.4 (br s, 0.6H), 7.2 (m, 0.4H),5.3-5.2 (m, 0.6H), 5.2-5.1 (m, 0.4H), 4.25-4.15 (m, 0.6H), 4.1-4.0 (m,0.4H), 3.97 (s, 3H), 3.9-3.75 (m, 1H), 3.6-3.45 (m, 1H), 3.4-3.35 (m,0.6H), 3.15-3.0 (m, 0.4H), 2.5 (s, 1.8), 2.49 (s, 1.2H), 2.45-1.7 (m,3H), 1.2 (d, 1.8H), 1.0 (d, 1.2H); ESI-MS (m/z): 511.4 [M+1]⁺.

Compound 226:((2S,3R)-5,5-difluoro-3-methyl-2-(((5-(trifluoromethyl)pyrimidin-2-yl)amino)methyl)piperidin-1-yl)(1-methyl-4-(5-(trifluoromethyl)pyrimidin-2-yl)-1H-pyrazol-3-yl)methanone

¹H NMR (d₆-DMSO, 400 MHz) δ 9.2 (s, 0.6H), 9.0 (s, 1.4H), 8.75 (m,0.5H), 8.6 (m, 0.5H), 8.42 (br s, 1.4H), 8.3 (br s, 0.6H), 7.8 (m,0.7H), 7.6 (m, 0.3H), 5.2 (m, 0.3H), 4.85 (m, 0.7H), 4.05 (m, 1H), 3.95(s, 0.8H), 3.8 (s, 2.2H), 3.8-3.4 (m, 3H), 2.2-1.9 (m, 3H), 1.2 (d,0.8H), 0.85 (d, 2.2H); ESI-MS (m/z): 565.3 [M+1]⁺.

Compound 227:(4-(4-chloropyridin-2-yl)-1-methyl-1H-pyrazol-3-yl)((2S,3R)-5,5-difluoro-3-methyl-2-(((5-(trifluoromethyl)pyrimidin-2-yl)amino)methyl)piperidin-1-yl)methanone

¹H NMR (d₆-DMSO, 400 MHz) δ 8.55-8.35 (m, 3H), 8.2 (s, 1H), 8.0 (m,0.8H), 7.8 (m, 0.2H), 7.6 (d, 0.2H), 7.45 (d, 0.8H), 7.4 (dd, 0.2H), 7.3(dd, 0.8H), 5.1 (m, 0.2H), 4.8 (m, 0.8H), 4.3 (m, 1H), 3.7 (s, 0.8H),3.4 (s, 2.2H), 3.6-3.3 (m, 3H), 2.2-2.0 (m, 3H), 1.15 (d, 0.6H), 0.9 (d,2.4H); ESI-MS (m/z): 530.3 [M+1]⁺.

Compound 229:((2S,3R)-5,5-difluoro-3-methyl-2-(((5-(trifluoromethyl)pyrimidin-2-yl)amino)methyl)piperidin-1-yl)(1-methyl-4-(6-(trifluoromethyl)pyridin-2-yl)-1H-pyrazol-3-yl)methanone

¹H NMR (CDCl₃, 400 MHz) δ 8.6-8.4 (m, 2H), 8.1 (s, 0.7H), 8.05 (s,0.3H), 7.93 (s, 1H), 7.9-7.7 (m, 1H), 7.6-7.5 (m, 1H), 7.4 (br s, 0.7H),5.9 (br s, 0.3H), 5.3-5.1 (m, 1H), 4.4-4.3 (m, 0.7H), 4.2-3.9 (m, 1.2H),4.05 (s, 2H), 3.92 (s, 1H), 3.7-3.4 (m, 1.4H), 3.2-3.0 (m, 0.7H),2.5-2.1 (m, 2H), 2.1-1.7 (m, 1H), 1.2 (d, 1H), 1.0 (d, 2H); ESI-MS(m/z): 563.7 [M+1]⁺.

Compound 230:((2S,3R)-5,5-difluoro-3-methyl-2-(((5-(trifluoromethyl)pyrimidin-2-yl)amino)methyl)piperidin-1-yl)(1-methyl-4-(pyrimidin-5-yl)-1H-pyrazol-3-yl)methanone

¹H NMR (CDCl₃, 400 MHz) δ 9.1 (br d, 1H), 8.9-8.7 (m, 2H), 8.6-8.4 (m,2H), 7.65 (s, 1H), 7.6 (s, 1H), 7.25 (br s, 0.5H), 5.9 (br s, 0.5H),5.2-5.1 (m, 0.5H), 5.1-5.0 (m, 0.5H), 4.7-4.6 (m, 0.5H), 4.5-4.4 (m,0.5H), 4.2-3.9 (m, 1H), 4.05 (s, 1.5H), 3.9 (s, 1.5H), 3.9-2.7 (m,0.5H), 3.7-3.5 (m, 1.5H), 3.2-3.0 (m, 0.5H), 2.4-1.8 (m, 3H), 1.2 (d,1.6H), 1.0 (d, 1.4H); ESI-MS (m/z): 496.8 [M+1]⁺.

Compound 231:((2S,3R)-5,5-difluoro-3-methyl-2-(((5-(trifluoromethyl)pyrimidin-2-yl)amino)methyl)piperidin-1-yl)(5,6′-dimethyl-[2,3′-bipyridin]-2′-yl)methanone

¹H NMR (CDCl₃, 400 MHz) δ 8.8 (br s, 1H), 8.5 (s, 3H), 7.95 (d, 1H),7.6-7.5 (m, 2H), 7.3 (m, 1H), 5.1-5.0 (m, 1H), 4.25-4.15 (m, 1H),3.9-3.8 (m, 1H), 3.45-3.4 (m, 1H), 3.1-2.9 (m, 1H), 2.9-2.8 (m, 1H), 2.7(s, 3H), 2.4 (s, 3H), 2.1-2.0 (m, 2H), 1.0 (d, 3H); ESI-MS (m/z): 521.3[M+1]⁺.

Compound 232:((2S,3R)-5,5-difluoro-3-methyl-2-(((5-(trifluoromethyl)pyrimidin-2-yl)amino)methyl)piperidin-1-yl)(1-ethyl-4-(pyrimidin-2-yl)-1H-pyrazol-3-yl)methanone

¹H NMR (CDCl₃, 400 MHz) δ 8.9 (s, 2H), 8.6-8.3 (m, 3H), 7.4-7.0 (m, 2H),5.4-5.3 (m, 0.5H), 5.2-5.1 (0.5H), 4.4-4.3 (m, 2H), 4.3-4.1 (m, 1H),4.0-3.8 (m, 1H), 3.6-3.1 (m, 2H), 2.5-2.0 (m, 3H), 1.7-1.6 (m, 3H), 1.2(d, 1.6H), 1.0 (d, 1.4H); ESI-MS (m/z): 511.0 [M+1]⁺.

Compound 233:((2S,3R)-5,5-difluoro-3-methyl-2-(((5-(trifluoromethyl)pyrimidin-2-yl)amino)methyl)piperidin-1-yl)(1,5-dimethyl-4-(pyrimidin-2-yl)-1H-pyrazol-3-yl)methanone

¹H NMR (CDCl₃, 400 MHz) δ 8.9-8.8 (m, 2H), 8.6-8.45 (m, 2H), 7.6 (br s,0.6H), 7.15-7.05 (m, 1H), 6.85-6.8 (m, 0.4H), 5.35-5.3 (m, 0.4H),5.2-5.1 (m, 0.6H), 4.2-4.1 (m, 1H), 4.0-3.8 (m, 1H), 3.9 (s, 3H),3.6-3.55 (m, 0.4H), 3.5-3.4 (m, 0.6H), 3.3-3.2 (m, 0.4H), 3.1-3.0 (m,0.6H), 2.8 (s, 1.3H), 2.7 (s, 1.7H), 2.6-2.5 (m, 0.6H), 2.5-2.4 (m,0.4H), 2.3-2.15 (m, 1H), 2.1-1.8 (m, 1H), 1.2 (d, 1.3H), 1.05 (d, 1.7H);ESI-MS (m/z): 511.1 [M+1]⁺.

Compound 237:((2S,3R)-5,5-difluoro-3-methyl-2-(((5-(trifluoromethyl)pyrimidin-2-yl)amino)methyl)piperidin-1-yl)(1-isopropyl-4-(pyrimidin-2-yl)-1H-pyrazol-3-yl)methanone

¹H NMR (CDCl₃, 400 MHz) δ 8.80-8.78 (m, 2H), 8.54-8.42 (m, 2H),8.25-8.14 (m, 1H), 7.12-7.08 (m, 1H), 5.3-5.2 (m, 0.5H), 5.15-5.05 (m,0.5H), 4.60-4.54 (m, 1H), 4.2-4.1 (m, 0.5H), 4.1-4.0 (m, 0.5H),3.85-3.75 (m, 1H), 3.55-3.35 (m, 1H), 3.35-2.95 (m, 1H), 2.6-2.35 (m,1H), 2.3-2.05 (m, 1H), 1.57 (d, 6H), 1.19 (d, 1.7H), 0.98 (m, 1.3H) ppm;ESI-MS (m/z): 525.40 [M+1]⁺.

Compound 238:((2S,3R)-5,5-difluoro-3-methyl-2-(((5-(trifluoromethyl)pyrimidin-2-yl)amino)methyl)piperidin-1-yl)(4-(pyrimidin-2-yl)-1-(2,2,2-trifluoroethyl)-1H-pyrazol-3-yl)methanone

¹H NMR (CDCl₃, 400 MHz) δ 8.86-8.83 (m, 2H), 8.54-8.38 (m, 2H), 8.35 (s,0.5H), 8.22 (s, 0.5H), 7.19-7.13 (m, 1H), 7.1-7.0 (m, 0.5H), 6.85-6.75(m, 0.5H), 5.3-5.2 (m, 0.5H), 5.15-5.05 (m, 0.5H), 4.84-4.72 (m, 2H),4.15-4.0 (m, 0.5H), 4.0-3.95 (m, 0.5H), 3.8-3.7 (m, 1H), 3.6-3.5 (m,0.5H), 3.5-3.4 (m, 0.5H), 3.4-3.35 (m, 0.5H), 3.15-3.0 (m, 0.5H),2.6-2.5 (m, 0.5H), 2.4-2.3 (m, 0.5H), 2.25-2.1 (m, 1H), 1.20 (d, 1.5H),0.98 (d, 1.5H) ppm; ESI-MS (m/z): 565.70 [M+1]⁺.

Compound 239:((2S,3R)-2-(((5-ethylpyrimidin-2-yl)amino)methyl)-5,5-difluoro-3-methylpiperidin-1-yl)(5-(4-fluorophenyl)-2-methylthiazol-4-yl)methanone

¹H NMR (MeOD, 400 MHz) δ 8.03 (s, 2.0H), 7.40-7.36 (m, 2.0H), 7.16-7.08(m, 2.0H), 4.85-4.75 (m, 1.0H), 4.3-4.2 (m, 1.0H), 4.45-4.4 (m, 2.0H),3.30 (s, 2.0H), 2.5-2.4 (m, 5.0H), 1.9-1.8 (m, 2.0H), 1.18 (t, 3.0H),0.88 (d, 3.0H) ppm; ESI-MS (m/z): 490.43 [M+1]⁺.

Compound 240:((2S,3R)-5,5-difluoro-3-methyl-2-(((5-(trifluoromethyl)pyrimidin-2-yl)amino)methyl)piperidin-1-yl)(6-methyl-3-(2-methyl-2H-tetrazol-5-yl)pyridin-2-yl)methanone

The title compound was prepared following the same general procedure asdescribed in Compound 1 using6-methyl-3-(2-methyl-2H-tetrazol-5-yl)picolinic acid in Step 3. ¹H NMR(CDCl₃, 400 MHz) δ 8.43 (s, 2.0H), 8.31 (d, 1.0H), 7.31 (d, 1.0H),5.35-5.25 (m, 1.0H), 5.05-4.95 (m, 1.0H), 4.31 (s, 3.0H), 3.95-3.85 (m,1.0H), 3.85-3.75 (m, 1.0H), 3.4-3.3 (m, 1.0H), 3.1-2.95 (m, 1.0H), 2.69(s, 3.0H), 1.6-1.5 (m, 1.0H), 0.93 (d, 3.0H) ppm; ESI-MS (m/z): 512.4[M+1]⁺.

Compound 241:((2S,3R)-5,5-difluoro-3-methyl-2-(((5-(trifluoromethyl)pyrimidin-2-yl)amino)methyl)piperidin-1-yl)(1-methyl-4-(pyrimidin-4-yl)-1H-pyrazol-3-yl)methanone

¹H NMR (CDCl₃, 400 MHz) δ 9.20 (s, 1H), 8.65-8.62 (m, 1H), 8.55-8.4 (m,2H), 8.10 (s, 0.6H), 8.03 (s, 0.4H), 7.52-7.50 (m, 0.6H), 7.44-7.42 (m,0.4H), 6.4-6.3 (m, 0.4H), 5.3-5.2 (m, 0.4H), 5.15-5.05 (m, 0.6H),4.3-4.2 (m, 0.6H), 4.01 (s, 1.6H), 3.95 (s, 1.4H), 3.92-3.8 (m, 2H),3.55-3.4 (m, 1.3H), 3.15-3.0 (m, 0.7H), 2.5-2.35 (m, 0.4H), 2.35-2.25(m, 0.6H), 2.2-2.1 (m, 1.3H), 1.21 (d, 1.4H), 1.01 (d, 1.6H) ppm; ESI-MS(m/z): 497.3 [M+1]⁺.

Compound 242:((2S,3R)-5,5-difluoro-2-(((3-fluoro-5-(trifluoromethyl)pyridin-2-yl)amino)methyl)-3-methylpiperidin-1-yl)(4-(5-fluoropyrimidin-2-yl)-1-methyl-1H-pyrazol-3-yl)methanone

¹H NMR (CDCl₃, 400 MHz) δ 8.50 (s, 0.9H), 8.41 (s, 0.6H), 8.20 (s,0.4H), 8.13 (s, 0.5H), 8.09 (s, 0.3H), 8.02 (s, 0.4H), 7.31-7.27 (m,1.0H), 6.57 (br s, 0.5H), 6.25 (br s, 0.3H), 5.25-5.05 (m, 0.9H),4.15-4.05 (m, 1.0H), 3.97 (d, 3.0H), 3.8-3.65 (m, 1.0H), 3.45-3.3 (m,1.0H), 3.2-3.0 (m, 0.8H), 2.4-2.35 (m, 1.0H), 2.25-2.2 (m, 0.7H),2.2-2.1 (m, 1.0H), 2.05-1.95 (m, 1.0H), 1.22 (d, 1.3H), 0.98 (d, 1.7H)ppm; ESI-MS (m/z): 532.3 [M+1]⁺.

Compound 252:((2S,3R)-5,5-difluoro-3-methyl-2-(((5-(trifluoromethyl)pyrimidin-2-yl)amino)methyl)piperidin-1-yl)(5-fluoro-2-(2-methyl-2H-tetrazol-5-yl)phenyl)methanone

¹H NMR CDCl₃, 400 MHz) δ 8.5-8.4 (m, 1.8H), 8.4-8.3 (m, 0.2H), 8.2-8.1(m, 0.6H), 8.1-8.0 (m, 0.4H), 7.2-7.1 (m, 0.4H), 7.1-7.0 (m, 0.6H),7.0-6.9 (m, 1H), 5.4-5.25 (m, 0.8H), 5.1-5.0 (m, 0.8H), 4.37 (s, 2.0H),4.28 (s, 1.0H), 4.2-4.1 (m, 0.8H), 3.7-3.6 (m, 1H), 3.5-3.4 (m, 1.8H),2.35-2.2 (m, 1H), 2.2-2.05 (m, 1H), 2.0-1.9 (m, 2H), 1.85-1.7 (m, 2.0H),1.6-1.5 (m, 2H), 1.10 (d, 2.0H), 1.02 (d, 1.0H) ppm: ESI-MS (m/z):515.00 [M+1]⁺.

Compound 16:((2S,3R)-5,5-difluoro-3-methyl-2-(((5-(trifluoromethyl)pyrimidin-2-yl)amino)methyl)piperidin-1-yl)(6′-methyl-[2,3′-bipyridin]-2′-yl)methanone

Step 1:(3-bromo-6-methylpyridin-2-yl)((2S,3R)-5,5-difluoro-3-methyl-2-(((5-(trifluoromethyl)pyrimidin-2-yl)amino)methyl)piperidin-1-yl)methanone

The title compound was prepared following the same general procedure asdescribed in Compound 1 using 3-bromo-6-methylpicolinic acid in Step 3.ESI-MS (m/z): 508.06/510.08 [M+1]⁺.

Step 2:((2S,3R)-5,5-difluoro-3-methyl-2-(((5-(trifluoromethyl)pyrimidin-2-yl)amino)methyl)piperidin-1-yl)(6′-methyl-[2,3′-bipyridin]-2′-yl)methanone

To a solution of(3-bromo-6-methylpyridin-2-yl)((2S,3R)-5,5-difluoro-3-methyl-2-(((5-(trifluoromethyl)pyrimidin-2-yl)amino)methyl)piperidin-1-yl)methanone(1 eq) and 2-(tributylstannyl)pyridine (1.2 eq) in DMF was addedPd(PPh₃)₄ (10 mol %). The reaction mixture was heated to 120° C. for 2 hin a microwave reactor and then the mixture was cooled and concentrated.The crude was dissolved with EtOAc and washed with sat'd NaHCO₃, brine,dried (MgSO₄) and concentrated. The crude was purified by chromatographyon SiO2 (EtOAc/hex) to obtain the title compound. ESI-MS (m/z): 507.2[M+1]⁺.

Compounds 17, 54, and 99 were prepared in a manner analogous to that forCompound 16.

Compound 17:((2S,3R)-5,5-difluoro-3-methyl-2-(((5-(trifluoromethyl)pyrimidin-2-yl)amino)methyl)piperidin-1-yl)(6-methyl-3-(pyrimidin-2-yl)pyridin-2-yl)methanone

¹H NMR (CDCl₃, 400 MHz) δ 8.81-8.79 (m, 2H), 8.6 (br s, 1H), 8.55-8.50(m, 2H), 7.37-7.35 (m, 1H), 7.25-7.22 (m, 1H), 5.15-5.05 (m, 1H),4.15-4.05 (m, 1H), 3.9-3.8 (m, 1H), 3.4-3.35 (m, 1H), 3.15-2.95 (m, 1H),2.85-2.8 (m, 1H), 2.76 (s, 3H), 2.25-2.2 (m, 1H), 2.05-2.0 (m, 1H), 1.00(d, 3H) ppm; ESI-MS (m/z): 508.03 [M+1]⁺.

Compound 18:((2S,3R)-2-(((5-chloropyrimidin-2-yl)amino)methyl)-5,5-difluoro-3-methylpiperidin-1-yl)(6-methyl-3-(pyrimidin-2-yl)pyridin-2-yl)methanone

Step 1:(3-bromo-6-methylpyridin-2-yl)((2S,3R)-2-(((5-chloropyrimidin-2-yl)amino)methyl)-5,5-difluoro-3-methylpiperidin-1-yl)methanone

The title compound was prepared following the same general procedure asdescribed in Compound 1 using 2,5-dichloropyrimidine in Step 1 and3-bromo-6-methylpicolinic acid in Step 3. ESI-MS (m/z): 473.93/475.81[M+1]⁺.

Step 2:((2S,3R)-2-(((5-chloropyrimidin-2-yl)amino)methyl)-5,5-difluoro-3-methylpiperidin-1-yl)(6-methyl-3-(pyrimidin-2-yl)pyridin-2-yl)methanone

The title compound was prepared following the same general procedure asdescribed in Compound 16 using 2-(tributylstannyl)pyrimidine in Step 2.ESI-MS (m/z): 474.05 [M+1]⁺.

Compound 55:((2S,3R)-5,5-difluoro-3-methyl-2-(((5-(trifluoromethyl)pyrimidin-2-yl)amino)methyl)piperidin-1-yl)(5-methyl-2-(pyrimidin-2-yl)phenyl)methanone

Step 1:(2-bromo-5-methylphenyl)((2S,3R)-5,5-difluoro-3-methyl-2-(((5-(trifluoromethyl)pyrimidin-2-yl)amino)methyl)piperidin-1-yl)methanone

The title compound was prepared following the same general procedure asdescribed in Compound 1 using 2-bromo-5-methylbenzoic acid in Step 3.ESI-MS (m/z): 507.0/509.0 [M+1]⁺.

Step 2:((2S,3R)-5,5-difluoro-3-methyl-2-(((5-(trifluoromethyl)pyrimidin-2-yl)amino)methyl)piperidin-1-yl)(5-methyl-2-(pyrimidin-2-yl)phenyl)methanone

The title compound was prepared following the same general procedure asdescribed in Compound 16 using 2-(tributylstannyl)pyrimidine in Step 2.ESI-MS (m/z): 506.94 [M+1]⁺.

Compound 56:(5-chloro-2-(pyrimidin-2-yl)phenyl)((2S,3R)-5,5-difluoro-3-methyl-2-(((5-(trifluoromethyl)pyrimidin-2-yl)amino)methyl)piperidin-1-yl)methanone

Step 1:(5-chloro-2-iodophenyl)((2S,3R)-5,5-difluoro-3-methyl-2-(((5-(trifluoromethyl)pyrimidin-2-yl)amino)methyl)piperidin-1-yl)methanone

The title compound was prepared following the same general procedure asdescribed in Compound 1 using 2-bromo-5-chlorobenzoic acid in Step 3.ESI-MS (m/z): 575.0 [M+1]⁺.

Step 2:(5-chloro-2-(pyrimidin-2-yl)phenyl)((2S,3R)-5,5-difluoro-3-methyl-2-(((5-(trifluoromethyl)pyrimidin-2-yl)amino)methyl)piperidin-1-yl)methanone

The title compound was prepared following the same general procedure asdescribed in Compound 16 using 2-(tributylstannyl)pyrimidine in Step 2.ESI-MS (m/z): 526.92 [M+1]⁺.

Compound 57:(5-chloro-2-(pyrimidin-2-yl)phenyl)((2S,3R)-2-(((5-chloropyrimidin-2-yl)amino)methyl)-5,5-difluoro-3-methylpiperidin-1-yl)methanone

Step 1:(5-chloro-2-iodophenyl)((2S,3R)-2-(((5-chloropyrimidin-2-yl)amino)methyl)-5,5-difluoro-3-methylpiperidin-1-yl)methanone

The title compound was prepared following the same general procedure asdescribed in Compound 1 using 2,5-dichloropyrimidine in Step 1 and2-bromo-5-chlorobenzoic in Step 3. ESI-MS (m/z): 540.93 [M+1]⁺.

Step 2:(5-chloro-2-(pyrimidin-2-yl)phenyl)((2S,3R)-2-(((5-chloropyrimidin-2-yl)amino)methyl)-5,5-difluoro-3-methylpiperidin-1-yl)methanone

The title compound was prepared following the same general procedure asdescribed in Compound 16 using 2-(tributylstannyl)pyrimidine in Step 2.ESI-MS (m/z): 493.3 [M+1]⁺.

Compound 102:((2S,3R)-5,5-difluoro-2-(((4-methoxy-5-(trifluoromethyl)pyrimidin-2-yl)amino)methyl)-3-methylpiperidin-1-yl)(1-methyl-4-(pyridin-2-yl)-1H-pyrazol-3-yl)methanone

Step 1: (2S,3R)-benzyl5,5-difluoro-2-(((4-methoxy-5-(trifluoromethyl)pyrimidin-2-yl)amino)methyl)-3-methylpiperidine-1-carboxylate

The title compound was prepared following the same general procedure asdescribed in Compound 1 using2-chloro-4-methoxy-5-(trifluoromethyl)pyrimidine in Step 1. ESI-MS(m/z): 475.22 [M+1]⁺.

Step 2:N-(((2S,3R)-5,5-difluoro-3-methylpiperidin-2-yl)methyl)-4-methoxy-5-(trifluoromethyl)pyrimidin-2-amine

A mixture of (2S,3R)-benzyl5,5-difluoro-2-(((4-methoxy-5-(trifluoromethyl)pyrimidin-2-yl)amino)methyl)-3-methylpiperidine-1-carboxylateand 10% Pd/C and EtOAc was stirred under a balloon of hydrogen. Whenstarting material was consumed as judged by T.L.C. analysis, thereaction mixture was filtered through a pad of celite and washed withEtOAc. The organics were concentrated in vacuo to afford the titlecompound which was used without further purification. ESI-MS (m/z):341.06 [M+1]⁺.

Step 3:((2S,3R)-2-(((5-chloropyrimidin-2-yl)amino)methyl)-5,5-difluoro-3-methylpiperidin-1-yl)(5-fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone

The title compound was prepared following the same general procedure asdescribed in Compound 1, Step 3, using1-methyl-4-(pyridin-2-yl)-1H-pyrazole-3-carboxylic acid. ESI-MS (m/z):526.2 [M+1]⁺.

Compound 120:((2S,3R)-5,5-difluoro-3-methyl-2-(((5-(trifluoromethyl)pyrazin-2-yl)amino)methyl)piperidin-1-yl)(1-methyl-4-phenyl-1H-pyrazol-3-yl)methanone

Step 1: (2S,3R)-benzyl5,5-difluoro-3-methyl-2-(((5-(trifluoromethyl)pyrazin-2-yl)amino)methyl)piperidine-1-carboxylate

The title compound was prepared following the same general procedure asdescribed in Compound 1 using 2-chloro-5-(trifluoromethyl)pyrazine inStep 1. ESI-MS (m/z): 445.4 [M+1]⁺.

Step 2:N-(((2S,3R)-5,5-difluoro-3-methylpiperidin-2-yl)methyl)-5-(trifluoromethyl)pyrazin-2-aminehydrobromide

The title compound was prepared following the same general procedure asdescribed in Compound 1, Step 2. ESI-MS (m/z): 311.3 [M+1]⁺.

Step 3:((2S,3R)-5,5-difluoro-3-methyl-2-(((5-(trifluoromethyl)pyrazin-2-yl)amino)methyl)piperidin-1-yl)(1-methyl-4-phenyl-1H-pyrazol-3-yl)methanone

The title compound was prepared following the same general procedure asdescribed in Compound 1, Step 3, using1-methyl-4-phenyl-1H-pyrazole-3-carboxylic acid. ¹H NMR (CDCl₃, 400 MHz)δ 8.15 (s, 0.25H), 8.05 (s, 0.75H), 7.8 (s, 0.75H), 7.7 (s, 0.25H),7.2-7.1 (m, 6H), 6.4 (m, 0.8H), 5.1 (m, 0.2H), 5.0 (m, 0.26H), 4.75 (m,0.75H), 3.7-3.8 (m, 1H), 3.65 (s, 0.8H), 3.60 (s, 2.2H), 3.4-3.3 (m,2H), 2.75-2.9 (m, 1H), 1.8 (m, 1H), 1.3-1.5 (m, 2H), 1.0 (d, 0.85H),0.70 (d, 2.15H); ESI-MS (m/z): 495.07 [M+1]⁺.

Compound 162:((2S,3R)-5,5-difluoro-3-methyl-2-(((5-(trifluoromethyl)pyridin-2-yl)amino)methyl)piperidin-1-yl)(1-methyl-4-(4-methylpyridin-2-yl)-1H-pyrazol-3-yl)methanone

Step 1: (2S,3R)-benzyl5,5-difluoro-3-methyl-2-(((5-(trifluoromethyl)pyridin-2-yl)amino)methyl)piperidine-1-carboxylate

To a mixture of (2S,3R)-benzyl2-(aminomethyl)-5,5-difluoro-3-methylpiperidine-1-carboxylate (1 eq) andK₂CO₃ (2 eq) in DMF (20 mL) was added2-fluoro-5-(trifluoromethyl)pyridine (3 eq). The reaction was warmed to80° C. for 2 h wherein the starting material was judged consumed asindicated by reverse-phase analytical HPLC. The reaction was cooled, anddiluted with EtOAc, and water. The layers were separated, and theorganic phase was washed with water (3×), brine, dried (MgSO₄) andconcentrated. The crude residue was purified by chromatography on SiO₂(EtOAc/hex) to give the title compound as a near colorless oil whichsolidified. ESI-MS (m/z): 444.4 [M+1]⁺.

Step 2:N-(((2S,3R)-5,5-difluoro-3-methylpiperidin-2-yl)methyl)-5-(trifluoromethyl)pyridin-2-aminehydrobromide

To the carbamate from the previous step was added to 30% HBr in HOAc.The reaction was stirred at rt (1-3 h) until sm was consumed as judgedby HPLC analysis. The reaction was concentrated in vacuo to give thetitle compound as a pale yellow foam which was used withoutpurification. ESI-MS (m/z): 310.3 [M+1]⁺.

Step 3:((2S,3R)-5,5-difluoro-3-methyl-2-(((5-(trifluoromethyl)pyridin-2-yl)amino)methyl)piperidin-1-yl)(1-methyl-4-(4-methylpyridin-2-yl)-1H-pyrazol-3-yl)methanone

The title compound was prepared following the same general procedure asdescribed in Compound 1 using1-methyl-4-(4-methylpyridin-2-yl)-1H-pyrazole-3-carboxylic acid in Step3. ESI-MS (m/z): 509.22 [M+1]⁺.

Compound 183:((2S,3R)-5,5-difluoro-3-methyl-2-(((5-(trifluoromethyl)pyridin-2-yl)amino)methyl)piperidin-1-yl)(6-methyl-3-(pyrimidin-2-yl)pyridin-2-yl)methanone

Step 1:(3-bromo-6-methylpyridin-2-yl)((2S,3R)-5,5-difluoro-3-methyl-2-(((5-(trifluoromethyl)pyridin-2-yl)amino)methyl)piperidin-1-yl)methanone

The title compound was prepared following the same general procedure asdescribed in Compound 1 using 2-chloro-5-(trifluoromethyl)pyridine inStep 1 and 3-bromo-6-methylpicolinic acid in Step 3. ESI-MS (m/z):507.12/509.1 [M+1]⁺.

Step 4:((2S,3R)-5,5-difluoro-3-methyl-2-(((5-(trifluoromethyl)pyridin-2-yl)amino)methyl)piperidin-1-yl)(6-methyl-3-(pyrimidin-2-yl)pyridin-2-yl)methanone

The title compound was synthesized following the same general protocolas described for Compound 16 using(3-bromo-6-methylpyridin-2-yl)((2S,3R)-5,5-difluoro-3-methyl-2-(((5-(trifluoromethyl)pyridin-2-yl)amino)methyl)piperidin-1-yl)methanoneand 2-(tributylstannyl)pyrimidine. ESI-MS (m/z): 507.16 [M+1]⁺.

Compound 204:((2S,3R)-5,5-difluoro-3-methyl-2-(((5-(trifluoromethyl)pyridin-2-yl)oxy)methyl)piperidin-1-yl)(6-methyl-3-(2H-1,2,3-triazol-2-yl)pyridin-2-yl)methanone

Step 1: ((2S,3R)-5,5-difluoro-3-methylpiperidin-2-yl)methanol

A mixture of (2S, 3R)-benzyl5,5-difluoro-2-(hydroxymethyl)-3-methylpiperidine-1-carboxylate and 10%Pd/C and EtOAc were stirred under a balloon of H₂ until T.L.C. analysisindicated starting material had been consumed. The reaction was filteredthrough a celite pad washing with EtOAc. The organics were concentratedin vacuo to give the title compound which was used without furtherpurification. ¹H NMR (CD₃OD, 400 MHz) δ 3.5-3.65 (m, 2H), 3.05-3.15 (m,1H), 2.8-2.95 (m, 2H), 2.15-2.25 (m, 1H), 1.85-2.1 (m, 2H), 0.97-1.01(dm, 3H).

Step 2:((2S,3R)-5,5-difluoro-2-(hydroxymethyl)-3-methylpiperidin-1-yl)(6-methyl-3-(2H-1,2,3-triazol-2-yl)pyridin-2-yl)methanone

To a solution of ((2S,3R)-5,5-difluoro-3-methylpiperidin-2-yl)methanol(1 eq) and DIEA (4 eq) in DMF was added6-methyl-3-(2H-1,2,3-triazol-2-yl)picolinic acid (1.5 eq) followed byHATU (1.2 eq). The reaction was stirred at room temperature for 2 h, andthen diluted with 1M HCl and EtOAc. The layers were separated, and theorganic layer was washed with 1M HCl (2×), sat. aq. NaHCO₃ (2×), brine(1×), dried (MgSO₄) and concentrated in vacuo. The crude residue waspurified by chromatography on silica gel to give the title compound as acolorless solid. ESI-MS (m/z): 351.99 [M+1]⁺.

Step 3:((2S,3R)-5,5-difluoro-3-methyl-2-(((5-(trifluoromethyl)pyridin-2-yl)oxy)methyl)piperidin-1-yl)(6-methyl-3-(2H-1,2,3-triazol-2-yl)pyridin-2-yl)methanone

To a solution of((2S,3R)-5,5-difluoro-2-(hydroxymethyl)-3-methylpiperidin-1-yl)(6-methyl-3-(2H-1,2,3-triazol-2-yl)pyridin-2-yl)methanone(1 eq) and 2-fluoro-5-(trifluoromethyl)pyridine (4 eq) in DMF was addedNaH (1.5 eq). After 20 min, one drop of 1M HCl was added to quench thereaction, and the crude mixture was purified by reverse-phasepreparative HPLC to afford the title compound as a colorless solid.ESI-MS (m/z): 496.9 [M+1]⁺.

Compound 205:((2S,3R)-5,5-difluoro-3-methyl-2-(((5-(trifluoromethyl)pyridin-2-yl)oxy)methyl)piperidin-1-yl)(4-(4-fluorophenyl)-1-methyl-1H-pyrazol-3-yl)methanone

Step 1:((2S,3R)-5,5-difluoro-2-(hydroxymethyl)-3-methylpiperidin-1-yl)(4-(4-fluorophenyl)-1-methyl-1H-pyrazol-3-yl)methanone

The title compound was synthesized following the same general protocolas described for Compound 204 using((2S,3R)-5,5-difluoro-3-methylpiperidin-2-yl)methanol and4-(4-fluorophenyl)-1-methyl-1H-pyrazole-3-carboxylic acid. ESI-MS (m/z):368.09 [M+1]⁺.

Step 2:((2S,3R)-5,5-difluoro-3-methyl-2-(((5-(trifluoromethyl)pyridin-2-yl)oxy)methyl)piperidin-1-yl)(4-(4-fluorophenyl)-1-methyl-1H-pyrazol-3-yl)methanone

The title compound was synthesized following the same general protocolas described for Compound 204 using((2S,3R)-5,5-difluoro-2-(hydroxymethyl)-3-methylpiperidin-1-yl)(4-(4-fluorophenyl)-1-methyl-1H-pyrazol-3-yl)methanoneand 2-fluoro-5-(trifluoromethyl)pyridine. ESI-MS (m/z): 512.73 [M+1]⁺.

Compound 206:((2S,3R)-5,5-difluoro-3-methyl-2-(((5-(trifluoromethyl)pyridin-2-yl)oxy)methyl)piperidin-1-yl)(1-methyl-4-(5-methylpyridin-2-yl)-1H-pyrazol-3-yl)methanone

Step 1:((2S,3R)-5,5-difluoro-2-(hydroxymethyl)-3-methylpiperidin-1-yl)(1-methyl-4-(5-methylpyridin-2-yl)-1H-pyrazol-3-yl)methanone

The title compound was synthesized following the same general protocolas described for Compound 204 using((2S,3R)-5,5-difluoro-3-methylpiperidin-2-yl)methanol and1-methyl-4-(5-methylpyridin-2-yl)-1H-pyrazole-3-carboxylic acid. ESI-MS(m/z): 365.11 [M+1]⁺.

Step 2:(2S,3R)-5,5-difluoro-3-methyl-2-(((5-(trifluoromethyl)pyridin-2-yl)oxy)methyl)piperidin-1-yl)(1-methyl-4-(5-methylpyridin-2-yl)-1H-pyrazol-3-yl)methanone

The title compound was synthesized following the same general protocolas described for Compound 204 using((2S,3R)-5,5-difluoro-2-(hydroxymethyl)-3-methylpiperidin-1-yl)(1-methyl-4-(5-methylpyridin-2-yl)-1H-pyrazol-3-yl)methanoneand 2-fluoro-5-(trifluoromethyl)pyridine. ESI-MS (m/z): 510.14 [M+1]⁺.

Compounds 207, 222-223, and 244-248 were prepared in a manner analogousto that for Compound 204.

Compound 207:((2S,3R)-5,5-difluoro-3-methyl-2-(((5-(trifluoromethyl)pyridin-2-yl)oxy)methyl)piperidin-1-yl)(5-(4-fluorophenyl)-2-methylthiazol-4-yl)methanone

¹H NMR (CDCl₃, 400 MHz) δ 8.45 (s, 0.4H), 8.30 (s, 0.6H), 7.77-7.72 (m,1H), 7.46-7.40 (m, 2H), 7.11-7.07 (m, 1H), 6.97-6.92 (m, 1H), 6.76-6.72(m, 1H), 5.2 (br s, 0.4H), 5.0-4.9 (m, 0.6H), 4.75-4.7 (m, 0.5H),4.6-4.5 (m, 0.5H), 4.40-4.37 (m, 0.6H), 4.10 (br s, 0.5H), 3.85-3.75 (m,0.5H), 3.50-3.35 (m, 0.5H), 3.15-3.05 (m, 0.5H), 2.69 (s, 1.3H), 2.59(s, 1.7H), 2.30-2.20 (m, 0.7H), 2.15-1.90 (m, 2H), 1.85-1.6 (m, 1H),1.15 (d, 1.3H), 0.86 (d, 1.7H) ppm; ESI-MS (m/z): 530.25 [M+1]⁺.

Compound 222:((2S,3R)-5,5-difluoro-3-methyl-2-(((5-(trifluoromethyl)pyrimidin-2-yl)oxy)methyl)piperidin-1-yl)(1-methyl-4-(pyrimidin-2-yl)-1H-pyrazol-3-yl)methanone

¹H NMR (CDCl₃, 400 MHz) δ 8.80 (s, 1.3H), 8.70 (s, 0.7H), 8.59-8.57 (m,0.7H), 8.48-8.46 (m, 1.3H), 8.11 (s, 0.7H), 8.06 (s, 0.3H), 7.05-6.95(m, 0.4H), 6.96-6.93 (m, 0.6H), 5.35-5.15 (m, 1H), 4.95-4.88 (m, 1.4H),4.68-4.65 (m, 0.6H), 3.98 (s, 2.1H), 3.88 (s, 0.9H), 3.85-3.75 (m, 1H),3.7-3.55 (m, 1H), 2.5-2.4 (m, 1H), 2.2-2.05 (m, 2H), 1.20 (s, 2.1H),0.96 (d, 0.9H) ppm; ESI-MS (m/z): 498.3 [M+1]⁺.

Compound 223:((2S,3R)-5,5-difluoro-3-methyl-2-(((5-(trifluoromethyl)pyrazin-2-yl)oxy)methyl)piperidin-1-yl)(1-methyl-4-(pyrimidin-2-yl)-1H-pyrazol-3-yl)methanone

¹H NMR (CDCl₃, 400 MHz) δ 8.6-8.58 (m, 1H), 8.56-8.49 (m, 0.6H),8.48-8.46 (m, 1H), 8.35-8.31 (m, 0.4H), 8.29-8.28 (m, 1H), 8.11 (s,0.6H), 7.99 (s, 0.4H), 7.05-7.02 (m, 0.5H), 6.98-6.95 (m, 0.5H),5.4-5.15 (m, 1H), 4.90-4.87 (m, 1H), 4.7-4.55 (m, 1H), 4.2-4.1 (m,0.4H), 3.96 (s, 1.7H), 3.9-3.8 (m, 0.6H), 3.76 (s, 1.3H), 3.55-3.4 (m,0.6H), 3.3-3.2 (m, 0.4H), 2.5-2.35 (m, 1H), 2.25-2.15 (m, 1H), 2.10-1.85(m, 1H), 1.20 (d, 1.7H), 0.96 (d, 1.3H) ppm; ESI-MS (m/z): 498.2 [M+1]⁺.

Compound 208:(4-(4-chlorophenyl)-1-methyl-1H-pyrazol-3-yl)((2S,3R)-5,5-difluoro-3-methyl-2-(((5-(trifluoromethyl)pyridin-2-yl)oxy)methyl)piperidin-1-yl)methanone

Step 1: (2S,3R)-benzyl5,5-difluoro-3-methyl-2-(((5-(trifluoromethyl)pyridin-2-yl)oxy)methyl)piperidine-1-carboxylate

To a mixture of (2S, 3R)-benzyl5,5-difluoro-2-(hydroxymethyl)-3-methylpiperidine-1-carboxylate (1 eq)and Cs₂CO₃ (2 eq) in DMF was added 2-fluoro-5-(trifluoromethyl)pyridine(5 eq). The reaction mixture was stirred at room temperature for 12 h,and then diluted with EtOAc and water. The layers were separated, andthe organic layer was washed with 1M HCl (2×), sat. aq. NaHCO₃ (2×),brine (1×), dried (MgSO₄) and concentrated in vacuo. Chromatography onSiO₂ (EtOAc/hex) afforded the title compound.

Step 2:2-(((2S,3R)-5,5-difluoro-3-methylpiperidin-2-yl)methoxy)-5-(trifluoromethyl)pyridine

To the carbamate from the previous step was added to 30% HBr in HOAc.The reaction was stirred at rt (1-3 h) until sm was consumed as judgedby HPLC analysis. The reaction was concentrated in vacuo to give thetitle compound as a pale yellow foam which was used withoutpurification. ESI-MS (m/z): 311.3 [M+1]⁺.

Step 3:(4-(4-chlorophenyl)-1-methyl-1H-pyrazol-3-yl)((2S,3R)-5,5-difluoro-3-methyl-2-(((5-(trifluoromethyl)pyridin-2-yl)oxy)methyl)piperidin-1-yl)methanone

To a solution of2-(((2S,3R)-5,5-difluoro-3-methylpiperidin-2-yl)methoxy)-5-(trifluoromethyl)pyridine(1 eq) and DIEA (4 eq) in DMF was added4-(4-chlorophenyl)-1-methyl-1H-pyrazole-3-carboxylic acid (1.5 eq)followed by HATU (1.2 eq). The reaction was stirred at room temperaturefor 2 h, and then diluted with 1M HCl and EtOAc. The layers wereseparated, and the organic layer was washed with 1M HCl (2×), sat. aq.NaHCO₃ (2×), brine (1×), dried (MgSO₄) and concentrated in vacuo. Thecrude residue was purified by chromatography on silica gel to give thetitle compound as a colorless solid. ¹H NMR (CDCl₃, 400 MHz) δ 8.46 (s,0.5H), 8.30 (s, 0.5H), 8.80-8.75 (m, 0.5H), 8.70-8.65 (m, 0.5H), 7.49(s, 0.5H), 7.42 (s, 0.5H), 7.36-7.26 (m, 3H), 7.17-7.15 (m, 1H),6.75-6.72 (m, 0.5H), 6.55-6.50 (m, 0.5H), 5.30 (br s, 0.5H), 5.05-4.95(m, 0.5H), 4.8-4.7 (m, 0.5H), 4.63-4.6 (m, 0.5H), 4.5-4.35 (m, 1H), 4.3(br s, 0.5H), 4.1-4.0 (m, 0.5H), 3.93 (s, 1.5H), 3.84 (s, 1.5H),3.45-3.3 (m, 0.5H), 3.2-3.05 (m, 0.5H), 2.4-2.25 (m, 0.5H), 2.23-2.2 (m,0.5H), 2.05-1.95 (m, 2H), 1.7-1.6 (m, 1H), 1.16 (d, 1.5H), 0.89 (d,1.5H) ppm; ESI-MS (m/z): 529.3 [M+1]⁺.

Compounds 212-214, 216, 220, and 243 were prepared in a manner analogousto that for Compound 208.

Compound 212:((2S,3R)-5,5-difluoro-3-methyl-2-(((5-(trifluoromethyl)pyridin-2-yl)oxy)methyl)piperidin-1-yl)(1-methyl-4-(pyrimidin-2-yl)-1H-pyrazol-3-yl)methanone

¹H NMR (CDCl₃, 400 MHz) δ 8.60 (d, 0.7H), 8.51 (s, 0.7H), 8.42 (d,1.3H), 8.35 (s, 0.3H), 8.15-8.10 (m, 1H), 7.81-7.78 (m, 1H), 7.05-7.0(m, 0.4H), 6.95-6.92 (m, 0.6H), 6.84-6.80 (m, 1H), 5.30-5.15 (m, 1.2H),4.86 (m, 1.3H), 4.56 (m, 0.8H), 4.2-4.05 (m, 0.6H), 3.97 (s, 2H), 3.84(s, 1H), 3.82-3.7 (m, 1H), 3.65-3.5 (m, 0.6H), 3.35-3.2 (m, 0.4H),2.5-2.3 (m, 1.4H), 2.25-2.05 (m, 1.6H), 1.19 (d, 2H), 0.95 (d, 1H) ppm;ESI-MS (m/z): 497.3 [M+1]⁺.

Compound 213:((2S,3R)-5,5-difluoro-3-methyl-2-(((5-(trifluoromethyl)pyridin-2-yl)oxy)methyl)piperidin-1-yl)(2-methyl-5-(pyrimidin-2-yl)thiazol-4-yl)methanone

¹H NMR (CDCl₃, 400 MHz) δ 8.64-8.63 (m, 0.7H), 8.51-8.48 (m, 2H), 8.33(s, 0.3H), 7.82-7.78 (m, 1H), 7.09-7.05 (m, 0.4H), 7.01-6.95 (m, 0.6H),6.83-6.8 (m, 1H), 5.25-5.15 (br m, 1H), 4.90-4.87 (m, 1.3H), 4.57-4.54(m, 0.7H), 3.95 (br s, 0.4H), 3.75-3.55 (m, 1.4H), 3.4-3.25 (m, 0.4H),2.76 (s, 2H), 2.64 (s, 1H), 2.5-2.3 (m, 1H), 2.25-2.1 (m, 2H), 2.05-1.95(m, 1.4H), 1.9-1.7 (m, 1.8H), 1.7-1.6 (m, 0.6H), 1.19 (d, 2H), 0.96 (d,1H) ppm; ESI-MS (m/z): 514.08 [M+1]⁺.

Compound 214:((2S,3R)-5,5-difluoro-3-methyl-2-(((5-(trifluoromethyl)pyridin-2-yl)oxy)methyl)piperidin-1-yl)(2-methyl-5-(pyridin-2-yl)thiazol-4-yl)methanone

¹H NMR (CDCl₃, 300 MHz) δ 8.77-8.73 (m, 1H), 8.46-8.41 (m, 2H),7.90-7.82 (m, 1H), 7.48-7.45 (m, 1H), 7.34-7.28 (m, 1H), 7.0-6.9 (m,0.6H), 5.35-5.30 (m, 0.7H), 5.05-4.95 (m, 0.8H), 4.85-4.70 (m, 3H),4.5-4.3 (m, 1H), 3.8-3.6 (m, 0.9H), 3.5-3.3 (m, 1H), 2.98 (s, 1.5H),2.90 (s, 1.5H), 2.5-2.3 (m, 1H), 2.25-2.1 (m, 2H), 2.05-1.95 (m, 2H),1.80-1.70 (m, 3H), 1.20 (d, 2H), 0.88 (d, 1H) ppm; ESI-MS (m/z): 513.3[M+1]⁺.

Compound 216:(5-chloro-2-(2-methyl-2H-tetrazol-5-yl)phenyl)((2S,3R)-5,5-difluoro-3-methyl-2-(((5-(trifluoromethyl)pyridin-2-yl)oxy)methyl)piperidin-1-yl)methanone

¹H NMR (CDCl₃, 400 MHz) δ 8.50-8.36 (m, 1.0H), 8.15-8.05 (m, 1.0H),7.92-7.75 (m, 1.0H), 7.55-7.35 (m, 3.0H), 7.0-6.8 (m, 1.0H), 5.4-5.3 (m,2.0H), 5.15-4.95 (m, 1.0H), 4.85-4.65 (m, 1.0H), 4.36 (s, 2.0H), 4.15(s, 1.0H), 3.90-3.8 (m, 0.4H), 3.7-3.4 (m, 1.2H), 3.25-3.05 (m, 0.3H),2.25-2.15 (m, 2.0H), 1.21 (d, 2.0H), 0.90 (d, 1.0H) ppm; ESI-MS (m/z):553.2 [M+Na]⁺.

Compound 220:((2S,3R)-5,5-difluoro-3-methyl-2-(((5-(trifluoromethyl)pyridin-2-yl)oxy)methyl)piperidin-1-yl)(1-methyl-4-(pyridin-2-yl)-1H-pyrazol-3-yl)methanone

¹H NMR (CDCl₃, 400 MHz) δ 8.6 (br s, 0.5H), 8.5 (br s, 0.5H), 8.4 (br s,0.5H), 8.3 (br s, 0.5H), 7.9-7.8 (m, 1H), 7.8-7.5 (m, 3H), 7.2 (m,0.5H), 7.05 (m, 0.5H), 6.8 (d, 0.5H), 6.6 (d, 0.5H), 5.4 (m, 0.5H), 5.1(m, 0.5H), 4.9-4.7 (m, 1H), 4.6-4.4 (m, 1H), 4.35 (m, 0.5H), 4.0 (m,0.5H), 3.95 (s, 1.5H), 3.8 (s, 1.5H), 3.6-3.5 (m, 0.5H), 3.3-3.2 (m,0.5H), 2.4-1.7 (m, 3H), 1.2 (d, 1.5H), 0.95 (d, 1.5H); ESI-MS (m/z):496.0 [M+1]⁺.

Compound 243:((2S,3R)-5,5-difluoro-3-methyl-2-(((5-(trifluoromethyl)pyridin-2-yl)oxy)methyl)piperidin-1-yl)(1-methyl-4-phenyl-1H-pyrazol-3-yl)methanone

¹H NMR (CDCl₃, 400 MHz) δ 8.6-8.47 (m, 1.0H), 8.4-8.31 (m, 1.0H),7.94-7.89 (m, 1.0H), 7.85-7.75 (m, 0.5H), 7.7-7.6 (m, 1.5H), 7.6-7.45(m, 2.0H), 7.2-7.1 (m, 0.5H), 7.1-7.0 (m, 0.5H), 6.85-6.75 (m, 0.5H),6.55-6.5 (m, 0.5H), 5.4-5.35 (m, 0.5H), 5.1-5.0 (m, 0.5H), 4.85-4.7 (m,1.0H), 4.55-4.4 (m, 1.0H), 4.4-4.3 (m, 0.5H), 4.1-4.0 (m, 0.5H), 3.94(s, 1.5H), 3.85 (s, 1.5H), 3.6-3.55 (m, 0.5H), 3.3-3.15 (m, 0.5H),2.4-2.3 (m, 0.5H), 2.25-2.2 (m, 0.5H), 2.1-2.05 (m, 1.0H), 1.7-1.6 (m,1.0H), 1.19 (d, 1.5H), 0.93 (d, 1.5H) ppm; ESI-MS (m/z): 495.97 [M+1]⁺.

Compound 215:((2S,3R)-5,5-difluoro-3-methyl-2-(((5-(trifluoromethyl)pyridin-2-yl)oxy)methyl)piperidin-1-yl)(6-methyl-3-(pyrimidin-2-yl)pyridin-2-yl)methanone

Step 1:(3-bromo-6-methylpyridin-2-yl)((2S,3R)-5,5-difluoro-3-methyl-2-(((5-(trifluoromethyl)pyridin-2-yl)oxy)methyl)piperidin-1-yl)methanone

The title compound was synthesized following the same general protocolas described for Compound 208 using2-(((2S,3R)-5,5-difluoro-3-methylpiperidin-2-yl)methoxy)-5-(trifluoromethyl)pyridineand 3-bromo-6-methylpicolinic acid.

Step 2:((2S,3R)-5,5-difluoro-3-methyl-2-(((5-(trifluoromethyl)pyridin-2-yl)oxy)methyl)piperidin-1-yl)(6-methyl-3-(pyrimidin-2-yl)pyridin-2-yl)methanone

To a solution of(3-bromo-6-methylpyridin-2-yl)((2S,3R)-5,5-difluoro-3-methyl-2-(((5-(trifluoromethyl)pyridin-2-yl)oxy)methyl)piperidin-1-yl)methanone(1 eq) and 2-(tributylstannyl)pyrimidine (1.2 eq) in DMF was addedPd(PPh₃)₄ (10 mol %). The reaction mixture was heated to 120° C. for 2 hin a microwave reactor and then the mixture was cooled and concentrated.The crude was dissolved with EtOAc and washed with sat'd NaHCO₃, brine,dried (MgSO₄) and concentrated. The crude was purified by chromatographyon SiO2 (EtOAc/hex) to obtain the title compound. ¹H NMR (CDCl₃, 400MHz) δ 8.69-8.67 (m, 1.0H), 8.58-8.54 (m, 1.6H), 8.47-8.45 (m, 1.0H),8.45-8.4 (m, 0.4H), 7.74-7.72 (m, 1.0H), 7.3-7.27 (m, 1.0H), 7.2-7.15(m, 0.4H), 7.05-7.0 (m, 0.6H), 6.8-6.75 (m, 1.0H), 5.15-5.05 (m, 1.0H),4.85-4.8 (m, 1.0H), 4.7-4.6 (m, 1.0H), 3.8-3.75 (m, 0.5H), 3.6-3.45 (m,1.0H), 3.4-3.25 (m, 0.5H), 2.57 (s, 1.6H), 2.50 (s, 1.4H), 2.45-2.4 (m,0.4H), 2.4-2.3 (m, 0.6H), 2.2-2.0 (m, 2.0H), 1.12 (d, 1.6H), 0.86 (d,1.4H) ppm; ESI-MS (m/z): 508.4 [M+1]⁺.

Compound 228:((2S,3R)-5,5-difluoro-2-(((3-fluoro-5-(trifluoromethyl)pyridin-2-yl)amino)methyl)-3-methylpiperidin-1-yl)(1-methyl-4-(pyrimidin-2-yl)-1H-pyrazol-3-yl)methanone

Step 1: (2S,3R)-benzyl5,5-difluoro-2-(((3-fluoro-5-(trifluoromethyl)pyridin-2-yl)amino)methyl)-3-methylpiperidine-1-carboxylate

To a mixture of (2S,3R)-benzyl2-(aminomethyl)-5,5-difluoro-3-methylpiperidine-1-carboxylate (1 eq) andCs₂CO₃ (2 eq) in DMF (20 mL) was added2,3-difluoro-5-(trifluoromethyl)pyridine (3 eq). The reaction wasstirred at room temperature for 2 h wherein the starting material wasjudged consumed as indicated by reverse-phase analytical HPLC. Thereaction was cooled, and diluted with EtOAc, and water. The layers wereseparated, and the organic phase was washed with water (3×), brine,dried (MgSO₄) and concentrated. The crude residue was purified bychromatography on SiO₂ (EtOAc/hex) to give the title compound as a nearcolorless oil which solidified. ESI-MS (m/z): 462.2 [M+1]⁺.

Step 2:N-(((2S,3R)-5,5-difluoro-3-methylpiperidin-2-yl)methyl)-3-fluoro-5-(trifluoromethyl)pyridin-2-aminehydrobromide

To the carbamate from the previous step was added to 30% HBr in HOAc.The reaction was stirred at rt (1-3 h) until sm was consumed as judgedby HPLC analysis. The reaction was concentrated in vacuo to give thetitle compound as a pale yellow foam which was used withoutpurification. ESI-MS (m/z): 328.3 [M+1]⁺.

Step 3:((2S,3R)-5,5-difluoro-3-methyl-2-(((5-(trifluoromethyl)pyridin-2-yl)amino)methyl)piperidin-1-yl)(1-methyl-4-(4-methylpyridin-2-yl)-1H-pyrazol-3-yl)methanone

The title compound was prepared following the same general procedure asdescribed in Compound 1 using1-methyl-4-(pyrimidin-2-yl)-1H-pyrazole-3-carboxylic acid in Step 3. ¹HNMR (CDCl₃, 400 MHz) δ 8.65 (d, 1H), 8.6 (d, 1H), 8.25 (s, 0.5H), 8.2(s, 0.5H), 8.15 (s, 0.5H), 8.1 (s, 0.5H), 7.35-7.2 (m, 1H), 7.1 (m, 1H),6.7-6.6 (m, 1H), 5.35-5.2 (m, 1H), 4.35-4.25 (m, 0.5H), 4.15-4.05 (m,0.5H), 4.0 (s, 1.5H), 3.95 (s, 1.5H), 3.9-3.8 (m, 0.5H), 3.6-3.5 (m,0.5H), 3.5-3.3 (m, 1.5H), 3.2-3.05 (m, 0.5H), 2.5-2.4 (m, 1H), 2.2-2.1(m, 1H), 2-1.6 (m, 1H), 1.25 (d, 1.5H), 1.0 (d, 1.5H); ESI-MS (m/z):513.7 [M+1]⁺.

Compound 234:(3-(cyclopropylethynyl)-6-methylpyridin-2-yl)((2S,3R)-5,5-difluoro-3-methyl-2-(((5-(trifluoromethyl)pyrimidin-2-yl)amino)methyl)piperidin-1-yl)methanone

To a solution of(3-bromo-6-methylpyridin-2-yl)((2S,3R)-5,5-difluoro-3-methyl-2-(((5-(trifluoromethyl)pyrimidin-2-yl)amino)methyl)piperidin-1-yl)methanone(1 eq) and ethynylcyclopropane (1.2 eq) in diisopropylamine was addedCuI (0.1 eq), and Pd(Ph₃P)₂Cl₂ (5 mol %). The reaction was warmed to 85°C. for 14 h, and then cooled and concentrated. The crude was taken up inEtOAc and washed with sat. aq. NaHCO₃, brine, dried (Na₂SO₄) andconcentrated in vacuo. The crude was purified by chromatography on SiO₂(EtOAc/hex) to afford the title compound. ¹H NMR (MeOD, 400 MHz) S8.65-8.45 (m, 1.0H), 8.3-8.25 (s, 0.7H), 7.75-7.55 (m, 1.0H), 7.4-7.3(s, 0.3H), 7.25-7.05 (m, 1.0H), 5.4-5.3 (m, 0.7H), 4.05-3.95 (m, 1.0H),3.7-3.6 (m, 1.0H), 2.86 (s, 0.5H), 2.66 (s, 2.5H), 2.1-2.0 (m, 4.0H),1.65-1.55 (m, 1.0H), 1.45-1.4 (m, 1.0H), 1.23 (d, 0.5H), 1.07 (d, 2.5H),0.9-0.8 (m, 4.0H) ppm; ESI-MS (m/z): 494.4 [M+1]⁺.

Compound 235:((2S,3R)-5,5-difluoro-3-methyl-2-(((5-(trifluoromethyl)pyrimidin-2-yl)amino)methyl)piperidin-1-yl)(6-methyl-3-(prop-1-yn-1-yl)pyridin-2-yl)methanone

To a solution of(3-bromo-6-methylpyridin-2-yl)((2S,3R)-5,5-difluoro-3-methyl-2-(((5-(trifluoromethyl)pyrimidin-2-yl)amino)methyl)piperidin-1-yl)methanone(1 eq) and tributyl(prop-1-yn-1-yl)stannane (1.2 eq) in DMF was addedCsF (2 eq), CuI (0.1 eq), and Pd(Ph₃P)₄ (5 mol %). The reaction waswarmed to 80° C. for 12 h, and then cooled and concentrated. The crudewas taken up in EtOAc and washed with sat. aq. NaHCO₃, brine, dried(Na₂SO₄) and concentrated in vacuo. The crude was purified bychromatography on SiO₂ (EtOAc/hex) to afford the title compound. ¹H NMR(MeOD, 400 MHz) δ 8.50 (s, 1.0H), 8.27 (s, 1.0H), 8.57-8.54 (m, 1.0H),7.12-7.09 (m, 1.0H), 5.4-5.3 (m, 1.0H), 4.15-3.95 (m, 1.0H), 3.7-3.6 (m,1.0H), 3.6-3.4 (m, 2.0H), 2.65-2.55 (m, 1.0H), 2.5-2.4 (m, 1.0H), 2.34(s, 3.0H), 2.2-2.1 (m, 4.0H), 1.06 (d, 3.0H) ppm; ESI-MS (m/z): 468.32[M+1]⁺.

Compound 236:((2S,3R)-5,5-difluoro-3-methyl-2-(((5-(trifluoromethyl)pyrimidin-2-yl)amino)methyl)piperidin-1-yl)(3-ethynyl-6-methylpyridin-2-yl)methanone

The title compound was prepared following the same general protocol asdescribed for Compound 235 using tributyl(ethynyl)stannane. ¹H NMR(CDCl₃, 400 MHz) δ 8.51-8.47 (m, 2.0H), 7.95-7.85 (s, 0.7H), 7.81-7.71(m, 1.0H), 7.22-7.14 (m, 1.0H), 6.05-6.0 (m, 0.3H), 5.3-5.2 (m, 0.3H),5.15-5.05 (m, 0.7H), 3.90-3.7 (m, 2.0H), 3.55-3.45 (m, 0.5H), 3.4-3.3(m, 1.5H), 3.1-2.95 (m, 1.0H), 2.67 (s, 2.1H), 2.52 (s, 0.9H), 2.45-2.35(m, 1.0H), 2.25-2.15 (m, 1.0H), 1.95-1.80 (m, 1.0H), 1.20 (d, 0.9H),1.01 (d, 2.1H) ppm; ESI-MS (m/z): 454.27 [M+1]⁺.

Compound 251:((2S,3R)-5,5-difluoro-3-methyl-2-(((5-(trifluoromethyl)pyrimidin-2-yl)amino)methyl)piperidin-1-yl)(2-fluoro-3-methyl-6-(2H-1,2,3-triazol-2-yl)phenyl)methanone

To 2-fluoro-3-methyl-6-(2H-1,2,3-triazol-2-yl)benzoic acid in CH₂Cl₂ wasadded SOCl₂. The reaction was warmed to 50° C. for 3 h, and thenconcentrated in vacuo. A solution of this acid chloride in CH₂Cl₂ wasadded to a solution ofN-(((2S,3R)-5,5-difluoro-3-methylpiperidin-2-yl)methyl)-5-(trifluoromethyl)pyrimidin-2-aminehydrobromide and DIEA (4 eq) in CH₂Cl₂. The reaction was stirred at roomtemperature until starting piperidine was consumed by HPLC analysis. Thereaction was concentrated in vacuo, and then taken up in EtOAc andwashed with 1M HCl, sat. aq. NaHCO₃, brine, dried (MgSO₄) andconcentrated. Purification by chromatography on SiO₂ (EtOAc/hex)provided the title compound as a solid. ESI-MS (m/z): 514.1 [M+1]⁺.

Synthesis of Compound 185 and Compound 129 Compound 185:((2S,3R)-5,5-difluoro-3-methyl-2-(((5-(trifluoromethyl)pyridin-2-yl)amino)methyl)piperidin-1-yl)(5-(4-fluorophenyl)-2-methylthiazol-4-yl)methanone

Step 1: (2S,3R)-benzyl5,5-difluoro-3-methyl-2-(((5-(trifluoromethyl)pyridin-2-yl)amino)methyl)piperidine-1-carboxylate.To a mixture of the crude amine compound r (1 eq) and K₂CO₃ (2 eq) inDMF (20 mL) was added 2-fluoro-5-(trifluoromethyl)pyridine (3 eq). Thereaction was warmed to 80° C. for 2 h wherein the starting material wasjudged consumed as indicated by reverse-phase analytical HPLC. Thereaction was cooled, and diluted with EtOAc, and water. The layers wereseparated, and the organic phase was washed with water (3×), brine,dried (MgSO₄) and concentrated. The crude residue was purified bychromatography on SiO₂ (EtOAc/hex) to give the title compound as a nearcolorless oil which solidified. ESI-MS (m/z): 444.4 [M+1]⁺.Step 2:N-(((2S,3R)-5,5-difluoro-3-methylpiperidin-2-yl)methyl)-5-(trifluoromethyl)pyridin-2-aminehydrobromide. To the carbamate from the previous step was added to 30%HBr in HOAc. The reaction was stirred at rt (1-3 h) until sm wasconsumed as judged by HPLC analysis. The reaction was concentrated invacuo to give the title compound as a pale yellow foam which was usedwithout purification. ESI-MS (m/z): 310.3 [M+1]⁺.Step 3:((2S,3R)-5,5-difluoro-3-methyl-2-(((5-(trifluoromethyl)pyridin-2-yl)amino)methyl)piperidin-1-yl)(5-(4-fluorophenyl)-2-methylthiazol-4-yl)methanone.To a solution ofN-(((2S,3R)-5,5-difluoro-3-methylpiperidin-2-yl)methyl)-5-(trifluoromethyl)pyridin-2-aminehydrobromide (10 mg) in DMF (0.5 mL) was added DIEA (3 eq) followed by5-(4-fluorophenyl)-2-methylthiazole-4-carboxylic acid (6 mg) and HATU (8mg). The reaction was allowed to stir at room temperature for 15 h, andwas then diluted with EtOAc and washed with 1M HCl, sat aq. NaHCO₃,brine, dried (MgSO₄), and concentrated. The crude residue was purifiedby chromatography on silica gel (EtOAc/hex) to give the title compoundas a colorless oil which solidified. ESI-MS (m/z): 529.5 [M+1]⁺.

Compound 129:(4-(4-chlorophenyl)-1-methyl-1H-pyrazol-3-yl)((2S,3R)-5,5-difluoro-3-methyl-2-(((5-(trifluoromethyl)pyrazin-2-yl)amino)methyl)piperidin-1-yl)methanone

Step 1: (2S,3R)-benzyl5,5-difluoro-3-methyl-2-(((5-(trifluoromethyl)pyrazin-2-yl)amino)methyl)piperidine-1-carboxylate.To a mixture of the crude amine compound r (1 eq) and K₂CO₃ (2 eq) inDMF (20 mL) was added 2-chloro-5-(trifluoromethyl)pyrazine (1.5 eq). Thereaction was warmed to 80° C. for 2 h wherein the starting material wasjudged consumed as indicated by reverse-phase analytical HPLC. Thereaction was cooled, and diluted with EtOAc, and water. The layers wereseparated, and the organic phase was washed with water (3×), brine,dried (MgSO₄) and concentrated. The crude residue was purified bychromatography on SiO₂ (EtOAc/hex) to give the title compound as a paleyellow solid. ESI-MS (m/z): 445.4 [M+1]⁺.Step 2:N-(((2S,3R)-5,5-difluoro-3-methylpiperidin-2-yl)methyl)-5-(trifluoromethyl)pyrazin-2-aminehydrobromide. To the carbamate from the previous step was added to 30%HBr in HOAc. The reaction was stirred at rt (1-3 h) until sm wasconsumed as judged by HPLC analysis. The reaction was concentrated invacuo to give the title compound as a pale yellow foam which was usedwithout purification. ESI-MS (m/z): 311.3 [M+1]⁺.Step 3:(4-(4-chlorophenyl)-1-methyl-1H-pyrazol-3-yl)((2S,3R)-5,5-difluoro-3-methyl-2-(((5-(trifluoromethyl)pyrazin-2-yl)amino)methyl)piperidin-1-yl)methanone.The title compound was prepared following the same general procedure asthat described for Compound 1, Step 3 usingN-(((2S,3R)-5,5-difluoro-3-methylpiperidin-2-yl)methyl)-5-(trifluoromethyl)pyrazin-2-aminehydrobromide and 4-(4-chlorophenyl)-1-methyl-1H-pyrazole-3-carboxylicacid. Purification of the crude residue by chromatography on silica gel(EtOAc/hex) to give the title compound as a light yellow oil whichsolidified. ESI-MS (m/z): 529.9 [M+1]⁺.

Compounds 207, 208, 212, 213, 214, 215, 216, 220, 222, 223, and 228,were prepared in a manner analogous to that shown above for Compounds185 and 129.

Compound 207:((2S,3R)-5,5-difluoro-3-methyl-2-(((5-(trifluoromethyl)pyridin-2-yl)oxy)methyl)piperidin-1-yl)(5-(4-fluorophenyl)-2-methylthiazol-4-yl)methanone

¹H NMR (CDCl₃, 400 MHz) δ 8.45 (s, 0.4H), 8.30 (s, 0.6H), 7.77-7.72 (m,1H), 7.46-7.40 (m, 2H), 7.11-7.07 (t, 1H), 6.97-6.92 (t, 1H), 6.76-6.72(t, 1H), 5.2 (br s, 0.4H), 5.0-4.9 (m, 0.6H), 4.75-4.7 (m, 1H), 4.6-4.5(m, 0.5H), 4.40-4.37 (m, 1H), 4.10 (br s, 0.5H), 3.85-3.75 (m, 1H),3.50-3.35 (m, 0.5H), 3.15-3.05 (m, 0.5H), 2.69 (s, 1.3H), 2.59 (s,1.7H), 2.30-1.8 (m, 2H), 1.15 (d, 1.2H), 0.86 (d, 1.8H); ESI-MS (m/z):530.3 [M+1]⁺.

Compound 208:(4-(4-chlorophenyl)-1-methyl-1H-pyrazol-3-yl)((2S,3R)-5,5-difluoro-3-methyl-2-(((5-(trifluoromethyl)pyridin-2-yl)oxy)methyl)piperidin-1-yl)methanone

¹H NMR (CDCl₃, 400 MHz) δ 8.46 (s, 0.5H), 8.30 (s, 0.5H), 7.80-7.75 (dd,0.5H), 7.70-7.65 (dd, 0.5H), 7.49 (s, 0.5H), 7.42 (s, 0.5H), 7.36-7.26(m, 3H), 7.2 (d, 1H), 6.75 (d, 0.5H), 6.55 (d, 0.5H), 5.30 (br s, 0.5H),5.05-4.95 (m, 0.5H), 4.8-4.7 (m, 0.5H), 4.63-4.6 (m, 0.5H), 4.5-4.4 (m,1H), 4.3 (br s, 0.5H), 4.1-4.0 (m, 0.5H), 3.93 (s, 1.5H), 3.84 (s,1.5H), 3.45-3.3 (m, 0.5H), 3.2-3.05 (m, 0.5H), 2.3-2.25 (m, 0.5H),2.23-2.2 (m, 0.5H), 2.05-1.7 (m, 2H), 1.16 (d, 1.5H), 0.89 (d, 1.5H);ESI-MS (m/z): 529.3 [M+1]⁺.

Compound 212:((2S,3R)-5,5-difluoro-3-methyl-2-(((5-(trifluoromethyl)pyridin-2-yl)oxy)methyl)piperidin-1-yl)(1-methyl-4-(pyrimidin-2-yl)-1H-pyrazol-3-yl)methanone

¹H NMR (CDCl₃, 400 MHz) δ 8.60 (d, 0.7H), 8.51 (s, 0.7H), 8.42 (d,1.3H), 8.35 (s, 0.3H), 8.15-8.10 (m, 1H), 7.81-7.78 (m, 1H), 7.05-7.0(m, 0.4H), 6.95-6.92 (m, 0.6H), 6.84-6.80 (m, 1H), 5.30-5.15 (m, 1H),4.86 (m, 1H), 4.56 (m, 1H), 4.2-4.05 (m, 0.3H), 3.97 (s, 2H), 3.84 (s,1H), 3.82-3.7 (m, 0.7H), 3.65-3.5 (m, 0.6H), 3.35-3.2 (m, 0.4H), 2.5-2.3(m, 1H), 2.25-2.05 (m, 2H), 1.19 (d, 2H), 0.95 (d, 1H); ESI-MS (m/z):497.3 [M+1]⁺.

Compound 213:((2S,3R)-5,5-difluoro-3-methyl-2-(((5-(trifluoromethyl)pyridin-2-yl)oxy)methyl)piperidin-1-yl)(2-methyl-5-(pyrimidin-2-yl)thiazol-4-yl)methanone

¹H NMR (CDCl₃, 400 MHz) δ 8.64-8.63 (d, 0.7H), 6.62 (br s, 0.7H), 8.5(d, 1.3H), 8.33 (s, 0.3H), 7.82-7.78 (m, 1H), 7.09-7.05 (t, 0.4H),7.01-6.95 (t, 0.6H), 6.83-6.8 (m, 1H), 5.25-5.15 (m, 1H), 4.90-4.87 (m,1.3H), 4.57-4.54 (m, 0.7H), 3.95 (m, 0.4H), 3.75-3.55 (m, 1.2H),3.4-3.25 (m, 0.4H), 2.76 (s, 2H), 2.64 (s, 1H), 2.5-2.3 (m, 1H), 2.4-1.8(m, 2H), 1.19 (d, 2H), 0.96 (d, 1H); ESI-MS (m/z): 514.08 [M+1]⁺.

Compound 214:((2S,3R)-5,5-difluoro-3-methyl-2-(((5-(trifluoromethyl)pyridin-2-yl)oxy)methyl)piperidin-1-yl)(2-methyl-5-(pyridin-2-yl)thiazol-4-yl)methanone

¹H NMR (CDCl₃, 300 MHz) δ 8.77-8.73 (m, 1H), 8.46-8.41 (m, 2H),7.90-7.82 (m, 1H), 7.48-7.45 (m, 1H), 7.34-7.28 (m, 1H), 7.0-6.9 (m,0.6H), 5.35-5.30 (m, 0.5H), 5.05-4.95 (m, 0.5H), 4.85-4.70 (m, 2.5H),4.5-4.3 (m, 0.5H), 3.8-3.6 (m, 0.5H), 3.5-3.3 (m, 0.5H), 2.98 (s, 1.5H),2.9 (s, 1.5H), 2.8-2.6 (s, 1H), 2.4-2.3 (m, 1H), 2.25-1.8 (m, 1H), 1.2(d, 2H), 0.9 (d, 1H); ESI-MS (m/z): 513.3 [M+1]⁺.

Compound 215:((2S,3R)-5,5-difluoro-3-methyl-2-(((5-(trifluoromethyl)pyridin-2-yl)oxy)methyl)piperidin-1-yl)(6-methyl-3-(pyrimidin-2-yl)pyridin-2-yl)methanone

¹H NMR (CDCl₃, 400 MHz) δ 8.67 (d, 1H), 8.63-8.55 (m, 1.6H), 8.5 (s,1H), 8.35 (br s, 0.4H), 7.8-7.7 (m, 1H), 7.35-7.25 (m, 1H), 7.25 (t,0.5H), 7.05 (t, 0.5H), 6.8 (t, 1H), 5.2-5.1 (m, 1H), 4.9-4.85 (m, 1H),4.7-4.6 (m, 1H), 3.8 (br s, 0.5H), 3.65-3.45 (m, 1H), 3.4-3.25 (m,0.5H), 2.6 (s, 1.6H), 2.5 (s, 1.4H), 2.5-2.3 (m, 1H), 2.2-1.9 (m, 2H),1.2 (d, 1.5H), 0.9 (d, 1.5H); ESI-MS (m/z): 508.4 [M+1]⁺.

Compound 216:(5-chloro-2-(2-methyl-2H-tetrazol-5-yl)phenyl)((2S,3R)-5,5-difluoro-3-methyl-2-(((5-(trifluoromethyl)pyridin-2-yl)oxy)methyl)piperidin-1-yl)methanone

ESI-MS (m/z): 531.3 [M+1]⁺.

Compound 220:((2S,3R)-5,5-difluoro-3-methyl-2-(((5-(trifluoromethyl)pyridin-2-yl)oxy)methyl)piperidin-1-yl)(1-methyl-4-(pyridin-2-yl)-1H-pyrazol-3-yl)methanone

¹H NMR (CDCl₃, 400 MHz) δ 8.6 (br s, 0.5H), 8.5 (br s, 0.5H), 8.4 (br s,0.5H), 8.3 (br s, 0.5H), 7.9-7.8 (m, 1H), 7.8-7.5 (m, 3H), 7.2 (m,0.5H), 7.05 (m, 0.5H), 6.8 (d, 0.5H), 6.6 (d, 0.5H), 5.4 (m, 0.5H), 5.1(m, 0.5H), 4.9-4.7 (m, 1H), 4.6-4.4 (m, 1H), 4.35 (m, 0.5H), 4.0 (m,0.5H), 3.95 (s, 1.5H), 3.8 (s, 1.5H), 3.6-3.5 (m, 0.5H), 3.3-3.2 (m,0.5H), 2.4-1.7 (m, 3H), 1.2 (d, 1.5H), 0.95 (d, 1.5H); ESI-MS (m/z):496.0 [M+1]⁺.

Compound 222:((2S,3R)-5,5-difluoro-3-methyl-2-(((5-(trifluoromethyl)pyrimidin-2-yl)oxy)methyl)piperidin-1-yl)(1-methyl-4-(pyrimidin-2-yl)-1H-pyrazol-3-yl)methanone

¹H NMR (CDCl₃, 400 MHz) δ 8.8 (s, 1.4H), 8.7 (s, 0.6H), 8.6 (d, 0.6H),8.5 (d, 1.4H), 8.15 (s, 0.7H), 8.1 (s, 0.3H), 7.2 (m, 0.5H), 7.0 (t,0.3H), 6.9 (t, 0.7H), 5.4-5.2 (m, 1H), 5.0-4.9 (m, 2H), 4.2-4.1 (m,0.3H), 4.0 (s, 2H), 3.9 (s, 1H), 3.9-3.8 (m, 0.7H), 3.75-3.6 (m, 0.7H),3.4 (m, 0.3H), 2.5-2.4 (m, 1H), 2.4-2.0 (m, 2H), 1.2 (d, 2H), 1.0 (d,1H); ESI-MS (m/z): 498.3 [M+1]⁺.

Compound 223:((2S,3R)-5,5-difluoro-3-methyl-2-(((5-(trifluoromethyl)pyrazin-2-yl)oxy)methyl)piperidin-1-yl)(1-methyl-4-(pyrimidin-2-yl)-1H-pyrazol-3-yl)methanone

¹H NMR (CDCl₃, 400 MHz) δ 8.65 (d, 1H), 8.6 (s, 0.5H), 8.5 (d, 1.5H),8.4 (s, 0.5H), 8.3 (s, 0.5H), 8.15 (s, 0.55H), 8.0 (s, 0.45H), 7.05 (t,0.4H), 7.0 (m, 0.6H), 5.4-5.35 (m, 0.5H), 5.3 (t, 0.5H), 4.9 (dd, 1H),4.7-4.6 (m, 1H), 4.25-4.15 (m, 0.5H), 4.0 (s, 1.6H), 3.9-3.8 (m, 0.5H),3.8 (s, 1.4H), 3.6-3.5 (m, 0.5H), 3.45-3.35 (m, 0.5H), 2.5-2.4 (m, 1H),2.3-1.9 (m, 2H), 1.2 (d, 1.6H), 1.0 (d, 1.4H); ESI-MS (m/z): 498.2[M+1]⁺.

Compound 228:((2S,3R)-5,5-difluoro-2-(((3-fluoro-5-(trifluoromethyl)pyridin-2-yl)amino)methyl)-3-methylpiperidin-1-yl)(1-methyl-4-(pyrimidin-2-yl)-1H-pyrazol-3-yl)methanone

¹H NMR (CDCl₃, 400 MHz) δ 8.65 (d, 1H), 8.6 (d, 1H), 8.25 (s, 0.5H), 8.2(s, 0.5H), 8.15 (s, 0.5H), 8.1 (s, 0.5H), 7.35-7.2 (m, 1H), 7.1 (m, 1H),6.7-6.6 (m, 1H), 5.35-5.2 (m, 1H), 4.35-4.25 (m, 0.5H), 4.15-4.05 (m,0.5H), 4.0 (s, 1.5H), 3.95 (s, 1.5H), 3.9-3.8 (m, 0.5H), 3.6-3.5 (m,0.5H), 3.5-3.3 (m, 1.5H), 3.2-3.05 (m, 0.5H), 2.5-2.4 (m, 1H), 2.2-2.1(m, 1H), 2-1.6 (m, 1H), 1.25 (d, 1.5H), 1.0 (d, 1.5H); ESI-MS (m/z):513.7 [M+1]⁺.

Compound 264:((2S,3R)-5,5-difluoro-3-methyl-2-(((5-(trifluoromethyl)pyrimidin-2-yl)amino)methyl)piperidin-1-yl)(4-(5-fluoropyrimidin-2-yl)-1,5-dimethyl-1H-pyrazol-3-yl)methanone

ES-MS (m/z): 529.1 [M+1]⁺.

TABLE 2 MS Characterization of Exemplary Compounds Compound # MS (m/z) 1500.2 2 466.19 3 501.2 4 517.1 5 496.2 6 462.2 7 510.2 8 511.2 9 477.210 516.2 11 482.2 12 497.1 13 463.25 14 507.2 15 473.2 16 507.2 17 508.218 474.05 19 531.2 20 455.2 21 495.16 22 461.15 23 513.2 24 509.15 25513.11 26 509.15 27 529.18 28 495.15 29 525.09 30 513.13 31 479.16 32509.18 33 529.1 34 495.19 35 525.14 36 496.08 37 462.2 38 514.15 39510.21 40 510.21 41 474.22 42 514.1 43 480.1 44 510.2 45 526.26 46510.16 47 526.22 48 512.2 49 514.09 50 480.06 51 506.2 52 472.05 53500.05 54 511.2 55 506.94 56 526.92 57 493.3 58 531.19 59 497.18 60526.14 61 542.08 62 542.05 63 526.11 64 526.09 65 512.2 66 530.13 67530.12 68 530.12 69 496.15 70 513.13 71 479.15 72 531.16 73 497.17 74527.19 75 527.13 76 527.08 77 527.2 78 543.08 79 531.17 80 543.13 81514.15 82 496.2 83 497.16 84 514.14 85 496.07 86 462.17 87 497.2 88463.15 89 510.2 90 496.2 91 512.13 92 478.12 93 496.06 94 462.06 95496.06 96 462.15 97 497.38 98 463.2 99 517.2 100 488.1 101 517.2 102526.2 103 543.09 104 543.16 105 543.15 106 543.16 107 539.19 108 539.26109 555.23 110 555.23 111 542.17 112 560.17 113 560.2 114 560.19 115556.2 116 556.19 117 556.2 118 572.23 119 572.19 120 495.07 121 513.05122 509.16 123 509.15 124 525.16 125 525.07 126 513.14 127 513.18 128529.09 129 529.13 130 496.23 131 514.13 132 510.22 133 510.28 134 510.19135 526.24 136 526.2 137 530.15 138 526.13 139 526.13 140 512.12 141542.1 142 542.14 143 530.07 144 530.07 145 526.08 146 531.1 147 527.2148 527.14 149 527.2 150 531.06 151 543.17 152 527.19 153 497.1 154516.1 155 496.16 156 497.15 157 496.1 158 496.06 159 497.24 160 512.04161 531.15 162 509.22 163 509.14 164 509.2 165 525.1 166 525.23 167495.2 168 511.17 169 512.13 170 494.15 171 512.11 172 512.1 173 508.09174 496.17 175 508.2 176 524.14 177 524.19 178 528.24 179 528.18 180515.2 181 510.21 182 530.16 183 507.16 184 513.06 185 529.14 186 525.11187 525.17 188 541.16 189 541.16 190 511.18 191 529.16 192 529.16 193525.14 194 526.14 195 512.1 196 526.17 197 526.05 198 526.18 199 542.17200 496.15 201 509.23 202 512.5 203 550.2 204 496.9 205 512.73 206510.14 207 530.25 208 529.3 210 494.95 211 513.2 212 497.3 213 514.08214 513.3 215 508.4 216 553.2 217 515.3 218 531.3 219 511.3 220 496.0221 529.9 222 498.3 223 498.2 224 497.32 225 511.4 226 565.3 227 530.3228 513.7 229 563.7 230 496.8 231 521.3 232 511.0 233 511.1 234 494.4235 468.32 236 454.27 237 525.40 238 565.70 239 490.43 240 512.4 241497.3 242 532.3 243 495.97 244 515.86 245 532.87 246 515.86 247 514.79248 514.79 249 531.35 250 500.19 253 511.2 254 461.06 264 529.1

Example 2: Orexin Receptor Cell-Based Functional Assay

Measurement of [Ca²⁺]i using a FLIPR: CHO-OX₁ or CHO-OX₂ cells wereseeded into black-walled clear-base 384-well plates (Corning, catalog#3712) at a density of 20,000 cells per well in F12-K mediumsupplemented with 10% FBS and then incubated in a 5% CO₂, 37° C.incubator overnight to reach 90% confluency. The cells were incubatedwith equal volume of calcium6 loading buffer (Molecular Devices, Inc.)containing 2.5 mM probenecid at 37° C. for 2 h, followed by testcompounds (dose-range 0.1 nM-10 μM) for another 30 min. The plates werethen placed into a FLIPR (Molecular Devices, Inc.) to monitorfluorescence (λ excitation 488 nm, λ emission 540 nm) before and afterthe addition of EC₉₀ of [OX]. Results for exemplary compounds ofFormulae (I), (Ia), (Ib), (II), (IIa), (III), (IIIa), (IV), (IVa), (V),or (Va) are shown in Table 3.

TABLE 3 IC₅₀ Bioactivity of Exemplary Compounds of the Application withRespect to OX₁ and OX₂ OX2, IC50 OXI, IC50 Compound # (nM) (nM)200 >5000 4 210 >5000 250 203 3700 >5000 202 >5000 150 97 >5000 1213 >5000 15 129 3500 4 33 4700 4 206 NT 22 205 >5000 52 187 3000 7186 >5000 6 177 170 6 197 >5000 3 175 4136 4 174 >5000 4 204 >5000 40147 >5000 5 148 >5000 6 45 >5000 47 48 >5000 607 29 >5000 4 135 >5000 19136 >5000 40 124 1000 4 125 >5000 4 139 >5000 10 125 >5000 2 138 >5000 6137 NT 5 132 >5000 7 63 >5000 3 134 >5000 4 123 >5000 2 133 >5000 1164 >5000 4 122 >5000 5 76 >5000 10 75 >5000 12 74 >5000 6 44 >5000 1024 >5000 385 26 >5000 4 32 >5000 12 39 >5000 1160 32 >5000 6 46 >5000 738 >5000 150 23 >5000 3 25 >5000 4 121 >5000 5 161 >5000 9 182 NT 1785 >5000 12 183 >5000 12 167 >5000 5 142 >5000 4 141 NT 6 151 >5000 11150 >5000 3 77 >5000 4 78 >5000 2 210 >5000 122 209 >5000 28095 >5000 >1000 93 >5000 156 96 >5000 >1000 158 >5000 62 157 >5000 18686 >5000 1388 85 >5000 30 156 >5000 >1000 87 >5000 >1000 155 >5000 38154 >5000 12 92 >5000 24 90 >5000 206 153 >5000 27 20 >5000 87 83 >500056 72 >5000 237 84 >5000 130 41 >5000 >5000 82 >5000 45 81 >5000 10242 >5000 >1000 22 >5000 7 211 >5000 2 130 >5000 6 120 >5000 2 21 >5000 289 >5000 23 91 >5000 7 19 >5000 10 15 >5000 46 14 >5000 52 17 >5000 870 >5000 5 31 >5000 4 30 >5000 3 101 1603 38 185 >5000 2 57 >5000 24169 >5000 2 36 >5000 19 100 >5000 9 18 >5000 18 52 >5000 9 53 >5000 294 >5000 81 12 >5000 15 16 >5000 60 51 >5000 4 55 >5000 30 56 >5000 750 >5000 20 9 >5000 6 6 >5000 8 8 >5000 8 11 >5000 8 7 >5000 7 10 >50007 5 >5000 10 1 >5000 192 54 >5000 43 49 >5000 6 67 1113 5 66 2076 165 >5000 2 69 >5000 9 68 >5000 8 215 >5000 5 216 >5000 4 217 >5000 4218 >5000 7 219 >5000 120 225 >5000 17 226 >5000 350 227 >5000 14228 >5000 14 229 >5000 7 220 >5000 8 221 >5000 2 222 >5000 26 223 >500052 224 >5000 62 230 >5000 74 231 >5000 14 232 >5000 82 233 >5000 1234 >5000 29 235 >5000 250 237 >5000 1700 238 >5000 >2000 239 >5000 29240 >5000 29 241 >5000 >1000 242 >5000 5 243 >5000 8 244 >5000 1000245 >5000 1000 246 >5000 4816 247 >5000 437 248 >5000 50 249 >5000 8252 >5000 8 254 >5000 70 263 >5000 57 264 >5000 3

Example 3: Nicotine Self-Administration Assay

For all experiments, rats weighing 250-300 g were housed in groups of1-23 per cage, in a temperature-controlled vivarium under a reversed12-h light/dark cycle (lights off at 8 am). Food and water were providedad libitum until behavioral training commences. During training, ratswere food-restricted to maintain ˜85-90% of their free-feeding bodyweight. Behavioral testing occurred during the dark portion of thelight/dark cycle between the hours of 9 am-1 pm, during the earlyportion of the dark phase of the cycle. All procedures were conducted instrict adherence with the National Institutes of Health Guide for theCare and Use of Laboratory Animals and were approved by theInstitutional Animal Care and Use Committee of The Scripps ResearchInstitute. Rats were anesthetized by inhalation of 1-3% isoflurane inoxygen and silastic catheters were inserted into the jugular veins.Briefly, the catheters consist of a 14 cm length of silastic tubingfitted to a guide cannula (Plastics One, Wallingford, Conn.), bent at acurved right angle and encased in dental acrylic. The catheter tubingwas passed subcutaneously from each animal's back to the right jugularvein, and 1 cm length of the catheter tip is inserted into the vein.After surgery, catheters are flushed daily with 0.1 mL of a heparinized(30 USP units/ml) sterile saline solution. Following 7 d of surgicalrecovery, rats were mildly food restricted to 85-90% of theirfree-feeding body weight and trained to press a lever in an operantchamber (Med Associates, St. Albans, Vt.) for food pellets (20 mg;TestDiet, Richmond, Ind.) under a fixed-ratio 5, time out 20 s (FR5TO20s) schedule of reinforcement prior to catheter implantation. Once stableresponding was achieved (>25 pellets per session), rats were permittedto acquire IV nicotine self-administration by autoshaping during 1-hdaily sessions, 7 days per week. Nicotine was delivered through thetubing into the IV catheter by a Razel syringe pump (Med Associates).Each nicotine self-administration session was performed using tworetractable levers (1 active; 1 inactive). Completion of the responsecriteria on the active lever resulted in the delivery of an IV nicotineinfusion (0.03 mg/kg/infusion). After 1 week, the nicotine dose wasincreased to 0.1 mg/kg/inf for the remainder of the experiment,including subsequent training and test sessions. Delivery of allnicotine infusions coincided with the initiation of a 20-s time-out (TO)period, signaled by a light cue located above the lever. During the TOperiod, responding on the lever was recorded but without scheduledconsequence. Catheter integrity was tested with the ultrashort-actingbarbiturate Brevital (methohexital sodium; Eli Lilly) at the end of theexperiment.

Example 4: Metabolic Stability and Intrinsic Clearances in RatHepatocytes

Stock solutions of compounds and control compounds were prepared in 10mM in appropriate solvent, such as DMSO. L-15 medium was placed in a 37°C. water bath and allowed to warm for at least 15 minutes prior to use.A quenching plate was prepared by adding 80 μL of acetonitrile to eachwell of a 96-well plate. In a new 96-well plate, the 10 mM stocksolution of test compounds and control compounds were diluted to 100 μMby combining 198 μL of acetonitrile and 2 μL of the 10 mM stock. A vialof cryopreserved rat hepatocytes were removed from storage andmaintained at cryogenic temperatures until thawing. The cells werethawed as quickly as possible, in a 37° C. water bath under gentleshaking. The vials were kept in the water bath until all ice crystalshave dissolved and are no longer visible. After the thawing wascompleted, the vials were sprayed with 70% ethanol and transferred to abiosafety cabinet. The contents of the vial were transferred into a 50mL conical tube containing L-15 medium. The conical tube was thencentrifuged at 50 g for 3 minutes at room temperature and a pellet wasformed at the bottom of the tube. After aspiration, the pellet wasresuspended with a small volume of buffer (˜200 μL) first and thendiluted to 50 mL in buffer for centrifugation. Upon completion of spinand aspiration, the pellet of hepatocytes was resuspended in enoughincubation medium to yield˜1.5×10⁶ cells/mL.

Cells were then counted with Cellometer® Vision. Cells with poorviability (<80% viability) were not acceptable for use. Counted cellswere then diluted with incubation medium to a working cell density of1.0×10⁶ viable cells/mL. 247.5 μL of hepatocytes were transferred intoeach wells of a 96-well cell culture plate and the plate was placed onan Eppendorf Thermomixer Comfort plate shaker to allow the hepatocytesto warm for 10 minutes. 2.5 μL of 100 μM test compound or controlcompounds were added into an incubation well containing cells and themixture was mixed to achieve a homogenous suspension at 0.5 min, whichwhen achieved, were defined as the 0.5 min time point. At the 0.5 mintime point, 20 μL incubated mixture was transferred to wells in a“Quenching plate” followed by vortexing. The quenching plate wasincubated at 37° C. at 900 rpm on an Eppendorf Thermomixer Comfort plateshaker. At 5, 15, 30, 45, 60, 80, 100 and 120 min, the incubation systemwas mixed and aliquots of samples (20 μL) were transferred and incubatedat each time point to wells in a separated “Quenching plate” followed byvortexing. The quenching plates were centrifuged for 20 minutes at 4,000rpm. Four different compounds were pooled into one cassette and used forLC/MS/MS analysis. All incubations were performed in singlicate.

All calculations were carried out using Microsoft Excel. Peak areas weredetermined from extracted ion chromatograms. in vitro half-life (t½) ofparent compound was determined by regression analysis of the Ln percentparent disappearance vs. time curve. The in vitro intrinsic clearance(in vitro Clint, in L/min/10⁶ cells) was determined from the slope valueusing the following equation: in vitro Clint=kV/N: V=incubation volume(0.25 mL); N=number of hepatocytes per well (0.25×10⁶ cells).

TABLE 4 Metabolic Stability and Intrinsic Clearances in Rat HepatocytesrHeps CLint Compound (ug/min/10{circumflex over ( )}6 # cells) 185 107129 3.8

Example 5: Metabolic Stability and Intrinsic Clearances in Human LiverMicrosomes

Human Liver Microsomes (HLM) were obtained from BD Gentest UltraPool 150donor (Lot no. 38289) at a concentration of 20 mg/mL protein. HLMs arestored in a −80° C. freezer. Prior to use, the pooled HLM were removedfrom the freezer and allowed to thaw in a 37° C. water bath and thenstored on wet ice. 100 μmol/L test compound solution and positivecontrol (PC) solutions (phenacetin, verapamil, diclofenac, imiprimine,benzydamine and metoprolol) were prepared by adding 2 μL of 10 mmol/Lstock solution in DMSO to 198 μL of acetonitrile. HML mixtures wereprepared by adding 1325 μL of 20 mg/mL HLM to 22260 μL of phosphatebuffer to obtain the HLM mixture at 1.1236 mg/mL. Prior to testing thecompounds, 222.5 μL of 1.1236 mg/mL HLM mixtures and 25 μL of the 10 mMNADPH were mixed in the incubation plates on a whirly mixer for 10seconds. The incubation plates were pre-warmed at 37° C. for 8 min. Thereaction was initiated with the addition of 2.5 μL of the 100 μM testcompound solutions or PC solutions to the incubation plate and thereaction solutions were mixed on a whirly mixer for 10 seconds andincubated at 37° C. 20 μL of reaction mixture was transferred at 0.5, 5,10, 15, 20, and 30 minutes into the quenching plate containing 100 μL ofcold acetonitrile. The quenching plates were then centrifuged at 4000rpm for 20 minutes and were placed at 4° C. for 30 minutes, thenre-centrifuged at 4000 rpm for 20 minutes to precipitate protein. 40 μLof supernatant of each compound was transferred into a 96-well analysisplate. 4 compounds were pooled together into one cassette and 160 μL ofpure water was added into each well. All incubations were performed insinglicate.

Quantitative LC-MS analysis were carried out with an API 4000 (AB sciex,USA) Ultra mass spectrometer at MRM mode (MS/MS). Peak areas weredetermined from extracted ion chromatograms. Percent parent remainingwas calculated from peak area of test compound or PC. The slope value,k, was determined by linear regression of the natural logarithm ofpercent parent remaining vs. incubation time curve. All calculationswere carried out using Microsoft Excel.

The in vitro half-life (in vitro t_(1/2)) was determined from the slopevalue: in vitro t½=−(0.693/k). Conversion of the in vitro t_(1/2) (inmin) into the in vitro intrinsic clearance (in vitro CLint, in μL/min/mgproteins) is done using the following equation:

${{in}{vitro}{CL}_{int}} = {( \frac{0.693}{( t_{1/2} )} )*{( \frac{{volume}{of}{incubation}({\mu L})}{{amount}{of}{protiens}({mg})} ).}}$

TABLE 5 Metabolic Stability and Intrinsic Clearances in Human LiverMicrosomes Compound hMics CLint # (ug/min/mg protein) 185 29 129 <3

The compounds described in this patent application show favorable ratand human in vitro metabolic stabilities (as measured in human livermicrosomes and rat hepatocytes) as well as good in vivo pharmacokineticproperties in rodents.

Example 6: Pharmacokinetic Evaluation Via Intravenous CassetteAdministration in Harlan RCC Strain of Wistar Rats

Two male Wistar rats (strain: Harlan RCC) of 10-12 weeks old on the dayof dosing were recruited and assigned as one study group. Each ratweighed 250-300 g on the day of dosing and was not fasted prior todosing. Rats were housed in a controlled environment (set up to maintain20-25° C. and 40-70% relative humidity). A 12-hour light/12-hour darkcycle was maintained except when interrupted by study-related events.The rats were dosed via IV bolus to tail vein over approximately 5seconds. Individual dosing values were calculated based on the rats'most recently recorded body weight. The dosing level was 0.5 mg/kg bodyweight (1 mL/kg with a concentration of 0.5 mg/mL). Rats were evaluatedduring in-life phase. The single dose formulation samples were collectedfrom the middle of formulation and stored at 5±3° C. for potentialanalysis. Samples (0.2 mL sample size) were collected from blood via acannulated tube in foot dorsal vein at 2 min, 5 min, 10 min, 30 min, 1h, 2 h, 4 h, 8 h, and 24 h post dosing. EDTA was used as ananticoagulant.

The blood samples were then centrifuged at 5 minutes at 4° C. to obtainplasma. Plasma samples were stored in polypropylene tubes, quicklyfrozen in ice box and kept at −80° C. Then the plasma samples weredeproteinated by solvent precipitation. Concentrations of test articlesin plasma and tissue samples were analyzed using a LC-MS/MS method with8-10 standards, 2× dilutions, with 10 ng/mL LOQ and 75% of standardswithin 25% of nominal; high, medium and low duplicate QCs were 5/6<25%error. WinNonlin version 6.2 was used for pharmacokinetic parameterscalculations. PK parameters including C₀, C_(max), T_(max), CL, Vss, Vz,T_(1/2), Tlast, AUC_(0-t), AUC_(0-infinity), AUC Extrap (%), and MRTusing non-compartmental model.

To determine terminal T_(1/2), the latest three time points withquantifiable concentration were used. T_(1/2) was reported as notcalculated, if the correlative coefficient (Rsq adjusted) was <0.85 atthe terminal phase. AUC were calculated using log trapezoidal method.

Example 7: Pharmacokinetics and Brain/Plasma Distribution in MaleSprague-Dawley Rats after Cassette Intravenous (Bolus) and OralAdministration

Male SD (Sprague-Dawley) rats, 250-300 g and 7-9 weeks old, wererecruited and assigned into two dose groups: Group #1 for intravenousadministration (IV) study and Group #2 for oral administration (PO, peros). In Group #1, rats were dosed at 0.5 mg/kg, (0.5 mg/kg for eachanalyte) with a dosing concentration of 0.5 mg/mL (of each analyte). Theformulation for IV dosing comprises: 5: 95 DMSO:SBE-β-CD (30% w/v) inwater. pH value was adjusted with 1M HCl (SBE is same as Captisol). Theformulation was administered via IV bolus at a dose volume of 1 mL/kgfor each single dose. Brains were harvested from rats at 15 min aftersecond dose on Day 2 of the study. In Group #2, rats were dosed at 1.0mg/kg (1 mg/kg for each analyte) with a dosing concentration of 0.2mg/mL (of each analyte). The formulation for PO dosing comprises: 0.5%HPMC, 0.1% Tween80 and were administrated via oral gavage at a level of5 mL/kg for each single dose. 150 μL of blood sample was collected pereach time point in both groups at 5, 10, 15, 30, 60, 120, 240, 360, 480,720 and 1440 min.

In a second arm study, plasma samples from each rat in both groups werecollected for PK study. Brain and plasma samples from Group #1administered an IV dose (0.5 mg/kg of each analyte as a cassette dose)were collected at 15 min post dose. Group #1 rats were dosed on secondday, after the last time point (24 h) has been collected from theinitial dose. Brain samples were weighed into appropriate size tubes sothey can be homogenized in the same vessel. Dose solutions andplasma/brain samples were stored at −80° C. until being analyzed.

Aliquots of dose formulation were diluted with appropriate solvent andanalyzed by LC/MS to obtain the concentrations of the analyte in thedosing solutions. The plasma samples from PK study were analyzed by aLC/MS/MS method developed by Frontage Laboratories according to FrontageBioanalytical Tier 2 criteria. The brain samples were homogenized in 0.1M phosphate buffer, pH 7.4 (1:3 volumes, brain:buffer) and an aliquotfrom each homogenate were further diluted 2-4 fold with control ratplasma before extracted by protein precipitation for analyses byLC/MS/MS. An aliquot of the brain homogenates (prepared in 0.1Mphosphate buffer only) were also subjected to equilibrium dialysis inRED device (6 h) and free brain concentrations were determined. At thesame time, LC/Ms/MS analyses of brain homogenates, plasma and samplesfrom the RED study (all from the IV dosed animals sacrificed at 15 minpost dose) were carried out. The concentrations of analytes present inplasma and brain were used to obtain brain/plasma ratio for eachcompound. The measured plasma concentrations of each analyte were usedto obtain the PK parameters using Phoenix® WinNonlin® software (version6.5.1).

INCORPORATION BY REFERENCE

All references cited in this application, and their references, areincorporated by reference herein in their entirety where appropriate forteachings of additional or alternative details, features, and/ortechnical background.

1. A compound of formula (I),

or a pharmaceutically acceptable salt thereof, wherein: X is halogen; X′is H or halogen; Z is NR² or O; A is aryl, aroyl, heteroaryl, orheteroaroyl, wherein A is optionally substituted with one or moresubstituents independently selected from the group consisting of alkyl,cycloalkyl, halo, —OH, alkoxy, —CN, —NR^(a)R^(b), —N(R^(a))C(O) alkyl,—N(R^(a))CO₂alkyl, —N(R^(a))SO₂alkyl, —C(O)alkyl, —CO₂H, —CO₂alkyl,—CONR^(a)R^(b), —SO₂alkyl, and —SO₂NR^(a)R^(b); wherein R^(a) and R^(b)are independently for each occurrence H or alkyl; B is aryl orheteroaryl, wherein B is optionally substituted with one or moresubstituents independently selected from the group consisting of alkyl,cycloalkyl, halo, —OH, alkoxy, —CN, —NR^(c)R^(d), —N(R^(c))C(O) alkyl,—N(R^(c))CO₂alkyl, —N(R^(c))SO₂alkyl, —C(O)alkyl, —CO₂H, —CO₂alkyl,—CONR^(c)R^(d), —SO₂alkyl, and —SO₂NR^(c)R^(d); wherein R^(c) and R^(d)are independently for each occurrence H or alkyl; E is aryl orheteroaryl, wherein E is optionally substituted with one or moresubstituents independently selected from the group consisting of alkyl,cycloalkyl, halo, —OH, alkoxy, —CN, —NR^(e)R^(f), —N(R^(e))C(O) alkyl,—N(R^(e))CO₂alkyl, —N(R^(e))SO₂alkyl, —C(O)alkyl, —CO₂H, —CO₂alkyl,—CONR^(e)R^(f), —SO₂alkyl, and —SO₂NR^(e)R^(f); wherein R^(e) and R^(f)are independently for each occurrence H or alkyl; n=1, 2, or 3; R¹ isalkyl; and R² is H or alkyl.
 2. The compound of claim 1, wherein A isaryl or heteroaryl.
 3. The compound of claim 1 or 2, wherein thecompound has the structure of formula (Ia):

or a pharmaceutically acceptable salt thereof.
 4. The compound of anyone of claims 1-3, wherein Z is NR².
 5. The compound of any one ofclaims 1-4, wherein R² is hydrogen.
 6. The compound of any one of claims1-4, wherein R² is methyl.
 7. The compound of any one of claims 1-6,wherein X is —F.
 8. The compound of any one of claims 1-7, wherein X′ is—F.
 9. The compound of any one of claims 1-8, wherein R¹ is C₁₋₄alkyl.10. The compound of any one of claims 1-9, wherein R¹ is methyl.
 11. Thecompound of any one of claims 1-10, wherein A is an optionallysubstituted monocyclic or bicyclic heteroaryl.
 12. The compound of anyone of claims 1-11, wherein A is selected from the list consisting ofpyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, and benzoxazolyl. 13.The compound of any one of claims 1-12, wherein A is pyridinyl.
 14. Thecompound of any one of claims 1-12, wherein A is pyrimidinyl.
 15. Thecompound of any one of claims 1-12, wherein A is pyrazinyl.
 16. Thecompound of any one of claims 1-12, wherein A is pyridazinyl.
 17. Thecompound of any one of claims 1-16, wherein A is unsubstituted.
 18. Thecompound of any one of claims 1-16, wherein A is optionally substitutedwith one or more substituents independently selected from the listconsisting of alkyl, alkoxy, and halo.
 19. The compound of any one ofclaims 1-16 or claim 18, wherein A is optionally substituted with one ormore substituents independently selected from the list consisting of —F,—Br, —Cl, —CF₃, methyl, ethyl, and methoxy.
 20. The compound of any oneof claims 1-16 or claim 18, wherein A is optionally substituted with oneor more substituents independently selected from the list consisting of—F, —Br, —Cl, —CHF₂, —CF₃, methyl, ethyl, and methoxy.
 21. The compoundof any one of claims 1-16 or claims 18-20 wherein A is monosubstituted.22. The compound of claim 21, wherein A is substituted with —CHF₂ or—CF₃.
 23. The compound of claim 21, wherein A is substituted with —CF₃.24. The compound of any one of claims 1-23, wherein B is an optionallysubstituted aryl.
 25. The compound of any one of claims 1-24, wherein Bis an optionally substituted phenyl.
 26. The compound of any one ofclaims 1-24, wherein B is an optionally substituted monocyclicheteroaryl or bicyclic heteroaryl.
 27. The compound of any one of claims1-23 or claim 26, wherein B is selected from the list consisting ofpyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, oxazolyl, isoxazolyl,imidazolyl, triazolyl, thiazolyl, thiophenyl, pyrazolyl, andbenzoimidazolyl.
 28. The compound of claim 27, wherein B is selectedfrom the list consisting of pyridinyl, thiophenyl, oxazolyl, thiazolyl,pyrazolyl, triazolyl, and benzoimidazolyl.
 29. The compound of any oneof claims 1-23 or claims 26-28, wherein B is pyridinyl.
 30. The compoundof any one of claims 1-23 or claims 26-28, wherein B is thiophenyl. 31.The compound of any one of claims 1-23 or claims 26-28, wherein B isoxazolyl.
 32. The compound of any one of claims 1-23 or claims 26-28,wherein B is thiazolyl.
 33. The compound of any one of claims 1-23 orclaims 26-28, wherein B is pyrazolyl.
 34. The compound of any one ofclaims 1-23 or claims 26-28, wherein B is triazolyl.
 35. The compound ofany one of claims 1-23 or claims 26-28, wherein B is benzoimidazolyl.36. The compound of any one of claims 1-35, wherein B is optionallysubstituted with one or more substituents independently selected fromthe group consisting of an alkyl, halo, alkoxy, and —CN.
 37. Thecompound of any one of claims 1-36, wherein B is optionally substitutedwith one or more substituents independently selected from the groupconsisting of —F, —Cl, —Br, —CN, methyl, ethyl, isopropyl, —CF₃,—CH₂CF₃, isopropoxy, and methoxy.
 38. The compound of claim 37, whereinB is substituted with one or more methyl.
 39. The compound of any one ofclaims 1-38, wherein B is monosubstituted.
 40. The compound of claim 39,wherein B is substituted with methyl.
 41. The compound of any one ofclaims 1-40, wherein E is an optionally substituted phenyl.
 42. Thecompound of any one of claims 1-40, wherein E is an optionallysubstituted monocyclic heteroaryl.
 43. The compound of any one of claims1-40 or 42, wherein E is selected from the group consisting oftriazolyl, tetrazolyl, pyrazolyl, pyridinyl, oxadiazolyl, pyrazinyl, andpyrimidinyl.
 44. The compound of any one of claims 1-40 or 42, wherein Eis triazolyl.
 45. The compound of any one of claims 1-40 or 42, whereinE is tetrazolyl.
 46. The compound of any one of claims 1-40 or 42,wherein E is pyrazolyl.
 47. The compound of any one of claims 1-40 or42, wherein E is pyridinyl.
 48. The compound of any one of claims 1-40or 42, wherein E isoxadiazolyl.
 49. The compound of any one of claims1-40 or 42, wherein E is pyrimidinyl.
 50. The compound of any one ofclaims 1-49, wherein E is optionally substituted with one or moresubstituents independently selected from the group consisting of alkyl,halo, and alkoxy.
 51. The compound of any one of claims 1-50, wherein Eis optionally substituted with one or more —F, —Cl, —Br, methoxy,methyl, ethyl, —CF₂H or —CF₃.
 52. The compound of claim 51, wherein E isoptionally substituted with one or more —F, —Cl, —Br, methoxy, methyl,ethyl, or —CF₃.
 53. The compound of any one of claims 1-52, wherein E isoptionally substituted with one or more methyl or —F.
 54. The compoundof any one of claims 1-53, wherein E is monosubstituted.
 55. Thecompound of any one of claims 1-49, wherein E is unsubstituted.
 56. Thecompound of any one of claims 1-23, wherein the fragment -B-E has thestructure

wherein: Y, independently for each occurrence, represents CH or N; andR³ represents alkyl, cycloalkyl, halo, —OH, alkoxy, —CN, —NR^(g)R^(h),—N(R^(g))C(O) alkyl, —N(R^(g))CO₂alkyl, —N(R^(g))SO₂alkyl, —C(O)alkyl,—CO₂H, —CO₂alkyl, —CONR^(g)R^(h), —SO₂alkyl, or —SO₂NR^(g)R^(h); whereinR^(g) and R^(h) are independently for each occurrence H or alkyl. 57.The compound of claim 56, wherein the structure

is selected from the following:


58. The compound of any one of claims 1-23 or claims 56-57, wherein thefragment -B-E has the structure


59. The compound of any one of claims 56-58, wherein R is alkyl oralkoxy.
 60. The compound of any one of claims 56-59, wherein R³ is —CH₃,—CF₃, or methoxy.
 61. The compound of any one of the claims 1-23 orclaims 56-57, wherein the fragment -B-E has the structure


62. The compound of claim 61, wherein R³ is CN, halo or alkyl.
 63. Thecompound of claim 62, wherein R³ is —F, —Cl, —CN, or methyl.
 64. Thecompound of any one of claims 1-23, wherein the fragment -B-E forms ahetero-aromatic ring structure of

wherein:

, independently for each occurrence, represents a single or double bond;W, independently for each occurrence, represents N, S, O, or CH; Vrepresents N or C; and R⁴ represents alkyl, cycloalkyl, halo, —OH,alkoxy, —CN, —NR^(i)R^(j), —N(R^(i))C(O) alkyl, —N(R^(i))CO₂alkyl,—N(R^(i))SO₂alkyl, —C(O)alkyl, —CO₂H, —CO₂alkyl, —CONR^(i)R^(j),—SO₂alkyl, or —SO₂NR^(i)R^(j); wherein R^(i) and R^(j) are independentlyfor each occurrence H or alkyl.
 65. The compound of claim 64, whereinthe structure

is selected from the following:


66. The compound of claim 64, wherein the structure

is


67. The compound of claim 64, wherein the structure

is


68. The compound of any one of claims 64-67, wherein R⁴ is C₁₋₄alkyl.69. The compound of claim 68, wherein R⁴ is methyl.
 70. The compound ofany of claims 1-3 or 7-69, wherein Z is O.
 71. The compound of any ofclaims 1-70, wherein n=1.
 72. The compound of claim 1, wherein thecompound has a structure of formula (II):

or a pharmaceutically acceptable salt thereof; wherein: m is 1, 2, or 3;R⁵ represents alkyl, cycloalkyl, halo, —OH, alkoxy, —CN, —NR^(j)R^(k),—N(R^(j))C(O) alkyl, —N(R^(j))CO₂alkyl, —N(R^(j))SO₂alkyl, —C(O)alkyl,—CO₂H, —CO₂alkyl, —CONR^(j)R^(k), —SO₂alkyl, or —SO₂NR^(j)R^(k); whereinR^(j) and R^(k) are independently for each occurrence H or alkyl; and X,X′, Z, B, E, n, R¹ and R² are as defined in claim
 1. 73. The compound ofclaim 1, wherein the compound has a structure of formula (III):

or a pharmaceutically acceptable salt thereof; wherein: m is 1, 2, 3 or4; R⁵ represents alkyl, cycloalkyl, halo, —OH, alkoxy, —CN,—NR^(j)R^(k), —N(R^(j))C(O) alkyl, —N(R^(j))CO₂alkyl, —N(R^(j))SO₂alkyl,—C(O)alkyl, —CO₂H, —CO₂alkyl, —CONR^(j)R^(k), —SO₂alkyl, or—SO₂NR^(j)R^(k); wherein R^(j) and R^(k) are independently for eachoccurrence H or alkyl; and X, X′, Z, B, E, n, R¹ and R² are as definedin claim
 1. 74. The compound of claim 1, wherein the compound has astructure of formula (IV):

or a pharmaceutically acceptable salt thereof; wherein: R⁶ representsalkyl, cycloalkyl, halo, —OH, alkoxy, —CN, —NR^(o)R^(p), —N(R^(o))C(O)alkyl, —N(R^(p))CO₂alkyl, —N(R^(o))SO₂alkyl, —C(O)alkyl, —CO₂H,—CO₂alkyl, —CONR^(o)R^(p), —SO₂alkyl, or —SO₂NR^(o)R^(p); wherein R^(o)and R^(p) are independently for each occurrence H or alkyl; and X, X′,Z, A, E, n, R¹ and R² are as defined in claim
 1. 75. The compound ofclaim 1, wherein the compound has a structure of formula (V):

or a pharmaceutically acceptable salt thereof, wherein: R⁶ representsalkyl, cycloalkyl, halo, —OH, alkoxy, —CN, —NR^(o)R^(p), —N(R^(o))C(O)alkyl, —N(R^(p))CO₂alkyl, —N(R^(o))SO₂alkyl, —C(O)alkyl, —CO₂H,—CO₂alkyl, —CONR^(o)R^(p), —SO₂alkyl, or —SO₂NR^(o)R^(p); wherein R^(o)and R^(p) are independently for each occurrence H or alkyl; and X, X′,Z, A, E, n, R¹ and R² are as defined in claim
 1. 76. The compound ofclaim 1, wherein the compound is compound 185,

or a pharmaceutically acceptable salt thereof.
 77. The compound of claim1, wherein the compound is compound 129,

or a pharmaceutically acceptable salt thereof.
 78. The compound of claim1, wherein the compound is compound 217,

or a pharmaceutically acceptable salt thereof.
 79. The compound of claim1, wherein the compound is compound 264,

or a pharmaceutically acceptable salt thereof.
 80. The compound of claim1, wherein the compound is compound 66,

or a pharmaceutically acceptable salt thereof.
 81. The compound of claim1, wherein the compound is compound 211,

or a pharmaceutically acceptable salt thereof.
 82. A compound selectedfrom the group consisting of compounds as shown in Table 1, andpharmaceutically acceptable salts thereof.
 83. A pharmaceuticalcomposition comprising (a) a compound of any of the preceding claims;and (b) a pharmaceutically acceptable excipient.
 84. A compound of anyone of claims 1-82 or a pharmaceutical composition of claim 83 for useas a medicament.
 85. A method of treating a disease or disorder mediatedby orexin receptor activity, comprising administering to a subject inneed of such treatment an effective amount of at least one compound ofany one of claims 1-82 or a pharmaceutical composition of claim
 83. 86.The method of claim 85, wherein the disease or disorder is selected fromthe group consisting of drug abuse or addiction, a sleep disorder, acognitive dysfunction in a psychiatric or neurologic disorder,depression, anxiety, panic disorder, post-traumatic stress disorder,seasonal affective disorder, schizophrenia, Alzheimer's disease,Parkinson's disease, Huntington's chorea, pain, epilepsy, behaviordisorder, mood disorder, manic depression, dementia, sex disorder, andpsychosexual disorder.
 87. The method of claim 86, wherein the drugabuse or addiction is selected from abuse of or addiction to cocaine,opiates, amphetamines, ethanol, cannabis/marijuana, or nicotine.
 88. Themethod of claim 85, wherein the disease or disorder is selected from thegroup consisting of an eating disorder, obesity, alcoholism or analcohol-related disorder, headache, migraine, gastrointestinal diseases,inflammations, immune-related diseases, ulcers, irritable bowelsyndrome, diarrhea, gastroesophageal reflux, endocrine-related diseases,cancer, hypertension, and renal disease.
 89. Use of a compound of any ofclaims 1-82 or a pharmaceutical composition of claim 83, in thepreparation of a medicament for the treatment of diseases or disordersregulated by orexin receptor activity, and the use of such compounds fortreatment of such diseases and disorders.
 90. The use of claim 89,wherein the disease or disorder is selected from the group consisting ofdrug abuse or addiction, a sleep disorder, a cognitive dysfunction in apsychiatric or neurologic disorder, depression, anxiety, panic disorder,post-traumatic stress disorder, seasonal affective disorder,schizophrenia, Alzheimer's disease, Parkinson's disease, Huntington'schorea, pain, epilepsy, behavior disorder, mood disorder, manicdepression, dementia, sex disorder, and psychosexual disorder.
 91. Theuse of claim 90, wherein the drug abuse or addiction is selected fromabuse of or addiction to cocaine, opiates, amphetamines, ethanol,cannabis/marijuana, or nicotine.
 92. The use of claim 89, wherein thedisease or disorder is selected from the group consisting of an eatingdisorder, obesity, alcoholism or an alcohol-related disorder, headache,migraine, gastrointestinal diseases, inflammations, immune-relateddiseases, ulcers, irritable bowel syndrome, diarrhea, gastroesophagealreflux, endocrine-related diseases, cancer, hypertension, and renaldisease.
 93. Use of a compound of any one of claims 1-82 or apharmaceutical composition of claim 83, in the preparation of amedicament for treating a disease or disorder in a patient in needthereof.
 94. The use of claim 93, wherein the disease or disorder isselected from the group consisting of drug abuse or addiction, a sleepdisorder, a cognitive dysfunction in a psychiatric or neurologicdisorder, depression, anxiety, panic disorder, post-traumatic stressdisorder, seasonal affective disorder, schizophrenia, Alzheimer'sdisease, Parkinson's disease, Huntington's chorea, pain, epilepsy,behavior disorder, mood disorder, manic depression, dementia, sexdisorder, and psychosexual disorder.
 95. The use of claim 94, whereinthe drug abuse or addiction is selected from abuse of or addiction tococaine, opiates, amphetamines, ethanol, cannabis/marijuana, ornicotine.
 96. The use of claim 93, wherein the disease or disorder isselected from the group consisting of an eating disorder, obesity,alcoholism or an alcohol-related disorder, headache, migraine,gastrointestinal diseases, inflammations, immune-related diseases,ulcers, irritable bowel syndrome, diarrhea, gastroesophageal reflux,endocrine-related diseases, cancer, hypertension, and renal disease. 97.A method of modulating the activity of an orexin receptor OX₁, OX₂, orboth, comprising contacting a cell comprising the orexin receptor withan effective amount of at least one compound of any one of claims 1-82or a pharmaceutical composition of claim
 83. 98. The method of claim 97,wherein the contacting is in vitro, ex vivo, or in vivo.
 99. A method oftreating a disease or disorder in a patient in need thereof, comprisingadministering a compound of any one of claims 1-82 or a pharmaceuticalcomposition of claim
 83. 100. The method of claim 99, wherein thedisease or disorder is selected from the group consisting of drug abuseor addiction, a sleep disorder, a cognitive dysfunction in a psychiatricor neurologic disorder, depression, anxiety, panic disorder,post-traumatic stress disorder, seasonal affective disorder,schizophrenia, Alzheimer's disease, Parkinson's disease, Huntington'schorea, pain, behavior disorder, mood disorder, manic depression,dementia, sex disorder, and psychosexual disorder.
 101. The method ofclaim 99, wherein the disease or disorder is selected from the groupconsisting of an eating disorder, obesity, alcoholism or analcohol-related disorder, headache, migraine, gastrointestinal diseases,inflammations, immune-related diseases, ulcers, irritable bowelsyndrome, diarrhea, gastroesophageal reflux, endocrine-related diseases,cancer, hypertension, and renal disease.
 102. The method of claim 99,wherein the disease or disorder is selected from the group consisting ofdrug abuse or addiction, panic disorder, anxiety, post-traumatic stressdisorder, pain, depression, seasonal affective disorder, an eatingdisorder, and hypertension.
 103. The method of claim 100 or 102, whereinthe drug abuse or addiction is selected from abuse of or addiction tococaine, opiates, amphetamines, ethanol, cannabis/marijuana, ornicotine.